Substituted 2-phenyl-3(2h)-pyridazinones

ABSTRACT

The invention relates to substituted 2-phenyl-3(2h)-pyridazinones, to a method for the production thereof, and to their use as medicaments used in the prophylaxis and/or treatment of diseases in humans and/or animals.

The invention relates to novel substituted 2-phenyl-3(2H)-pyridazinonederivatives, to processes for their preparation and to their use forproducing medicaments, in particular for controlling fibrotic disorders.

Lysyl oxidase is a copper-dependent amine oxidase (EC 1.4.3.13) whichoxidatively deaminates the peptidyl-lysine residues in collagen andelastin molecules [H. M. Kagan, Lysyloxidase: Mechanism, regulation andrelationship to liver fibrosis, Path. Res. Pract. 190, 910-919 (1994)].This results in the formation of stable covalent linkages oftropocollagen or tropoelastin, which makes the assembly of stablecollagen fibers from tropocollagen possible.

Lysyl oxidase plays a key role in disorders in which there is anincreased, deposition of collagen in the interstitial space. There is amany-fold increase in the activity of lysyl oxidase in patients withincreased interstitial collagen deposition compared with a normalhealthy population [R. C. Siegel, K. H. Chen, J. S. Greenspan, J. M.Aguiar, Biochemical and immunochemical study of lysyl oxidaseexperimental hepatic fibrosis in the rat, Proc. Natl. Acad. Sci. USA 752945-2949 (1978); A. Konishi, H. Iguchi, J. Ochi, R. Kinoshita, K.Miura, H. Uchino, Increased lysyl oxidase in culture-medium ofnon-parenchymal cells from fibrotic livers, Gastroenterol. 89, 709-715(1985)]. There was a measurable increase in the lysyl oxidaseconcentration in the serum from such patients [Y. Murawaki, Y. Kusakabe,C. Hirayama, Serum lysyl oxidase activity in chronic liver disease incomparison with serum levels of prolyl hydroxylase and laminin, Hepatol.14, 1167-1173 (1991)]. In addition, it was possible to showin-animal-models [S. Ricard-Blum, G. Ville, J. A. Grimaud, Hepaticpyridoline level in murine schistosomiasis, in: Molecular and cellbiology of liver fibrogenesis, edited by A. M. Gressner and G. Ramadori,Kluwer Academic Publishers, Dordrecht, 1992] and in patients [S.Ricard-Blum, S. Bresson-Hadni, D. A. Vuitton, G. Ville, J. A. Grimaud,Hydroxypyridinium collagen cross-links in human liver fibrosis: a studyof alveolar echinococcosis, Hepatol. 15, 599-602 (1992); A. Hayasaka, S.Iida, N. Suzuki, F. Kondo, M. Miyazaki, H. Yonemitsu, Pyridinolonecollagen cross-links in patients with chronic viral hepatitis andcirrhosis, J. Hepatol. 24, 692-698 (1996)] that reaction products oflysyl oxidase, the dipyridinium crosslinks, are detectable in greatlyincreased concentrations in fibrotic tissues. It was shown that thedegradability of deposited collagen depends on the degree of collagencrosslinking. Collagen with less crosslinking is more rapidly degradedby collagenase than is collagen with a high degree of crosslinking [C.A. Vater, E. D. Harris, R. C. Siegel, Native cross-links in collagenfibrils induce resistance to human human synovial collagenase, Biochem.J. 181, 639-645 (1979)].

Lysyl oxidase thus has a key role in the formation of pathologicalcollagen deposits through reducing the degradability of collagen fibers.Inhibition of lysyl oxidase activity thus leads to increased collagendegradation, so that the typical fibrotic tissue transformation can beprevented by inhibitors of lysyl oxidase.

It is an object of the present invention to provide medicaments for theprophylaxis and/or treatment of fibrotic disorders.

The object of the present invention is achieved by compounds of theformula (I), which act as lysyl oxidase inhibitors.

Structurally similar compounds are known for other indications and withdifferent mechanisms of action. Thus,4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone is described asnon-steroidal analgesic and as antiinflammatory active substance [J.Med. Chem. 22, 53 (1979); Jpn. Kokai Tokkyo Koho JP 02200634]. An effectof 5-(4-methylsulfonylphenyl)pyridazinones as selective COX-2 inhibitorsis described; they are suitable for controlling inflammatory orcyclooxygenase-mediated processes such as asthma or arthritis(WO-A-98/41511).

The present invention relates to compounds formula (I)

in which

-   R¹ is 5- to 7-membered, saturated or partially unsaturated    heterocyclyl which is linked via a ring nitrogen atom and optionally    has a further heteroatom or hetero chain member from the series N,    O, S, SO or SO₂, and which may be substituted once or twice,    identically or differently, by substituents selected from the group    of halogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,    hydroxy, oxo, carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl,    (C₃-C₈)-cycloalkylcarbonyl, (C₁-C₆)-alkylsulfonyl, aminocarbonyl,    and (C₁-C₆)-alkylaminocarbonyl,    -   where (C₁-C₆)-alkyl and (C₁-C₆)-alkanoyl in turn may each be        substituted by halogen, hydroxy, (C₁-C₄)-alkoxy,        (C₁-C₄)-alkoxycarbonyl, amino, mono- or di-(C₁-C₄)-alkylamino,        (C₁-C₄)-alkoxycarbonylamino or 5- or 6-membered heterocyclyl        having up to two heteroatoms from the series N, O and/or S,        or-   R¹ is 5-membered heteroaryl which is linked via a ring nitrogen atom    and has up to two further ring nitrogen atoms, and which may be    substituted once to three times, identically or differently, by    halogen, (C¹-C₆)-alkoxycarbonyl or (C₁-C₆)-alkyl which is in turn    optionally substituted by hydroxy or halogen,-   R² is (C₆-C₁₀)-aryl which may be substituted once or twice,    identically or differently, by substituents selected from the group    of halogen, nitro, cyano, (C¹-C₆)-alkyl, trifluoromethyl,    (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, hydroxy, (C₁-C₆)-acyloxy, amino,    (C₁-C₆)-acylamino, mono- and di-[(C₁-C₆)-alkyl-sulfonyl]amino,    -   where (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy in turn may each be        substituted by hydroxy, amino, (C₁-C₄)-alkoxy or        (C₁-C₄)-acylamino,        or-   R² is 5- or 6-membered heteroaryl which has up to two ring nitrogen    atoms and which may be substituted by amino, hydroxy, halogen,    (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy,    and-   R³ is hydrogen, halogen, (C₁-C₆)-alkyl, trifluoromethyl, nitro,    cyano, carboxyl or (C₁-C₆)-alkoxycarbonyl.

The compounds of the invention may also be present in the form of theirsalts, solvates or solvates of the salts.

The compounds of the invention may, depending on their structure, existin stereoisomeric forms (enantiomers, diastereomers). The inventiontherefore relates to the enantiomers or diastereomers and respectivemixtures thereof. The stereo-isomerically pure constituents can beisolated in a known manner from such mixtures of enantiomers and/ordiastereomers.

The invention also relates, depending on the structure of the compounds,to tautomers of the compounds.

Salts preferred for the purposes of the invention are physiologicallyacceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds of the inventioninclude acid addition salts of mineral acids, carboxylic acids andsulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalene-disulfonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, malicacid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds of the invention alsoinclude salts of conventional bases, such as by way of example andpreferably alkali metal salts (e.g. sodium and potassium salts),alkaline earth metal salts (e.g. calcium and magnesium salts) andammonium salts derived from ammonia or organic amines having 1 to 16 Catoms, such as by way of example and preferably ethylamine,diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,dihydroabiethylamine, arginine, lysine, ethylenediamine andmethylpiperidine.

Solvates refers for the purposes of the invention to those forms of thecompounds which form a complex in the solid or liquid state throughcoordination with solvent molecules. Hydrates are a specific form ofsolvates in which the coordination takes place with water.

For the purposes of the present invention, the substituents have thefollowing meaning unless specified otherwise:

(C₁-C₆)-alkanoyl is a straight-chain or branched alkanoyl radical having1 to 6 carbon atoms. Examples which may be mentioned as preferred are:formyl, acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl,isopentanoyl and hexanoyl. A straight-chain or branched alkanoyl radicalhaving 1 to 4 carbon atoms is preferred. Acetyl and propanoyl areparticularly preferred.

(C₁-C₆)- and (C₁-C₄) are a straight-chain or branched alkyl radicalhaving respectively 1 to 6 and 1 to 4 carbon atoms. Preference is givento a straight-chain or branched alkyl radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. Preferred exampleswhich may be mentioned are: methyl, ethyl, n-propyl, isopropyl,tert-butyl, n-pentyl and n-hexyl.

(C₂-C₆)- and (C₂-C₄)-alkenyl are a straight-chain or branched alkenylradical having respectively 2 to 6 and 2 to 4 carbon atoms. Preferenceis given to a straight-chain or branched alkenyl radical having 2 to 4,particularly preferably having 2 to 3, carbon atoms. Preferred exampleswhich may be mentioned are: vinyl, allyl, n-prop-1-en-1-yl andn-but-2-en-1-yl.

(C₁-C₆)- and (C₁-C₄)-alkoxy are a straight-chain or branched alkoxyradical having respectively 1 to 6 and 1 to 4 carbon atoms. Preferenceis given to a straight-chain or branched alkoxy radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. Preferred exampleswhich may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy,tert-butoxy, n-pentoxy and n-hexoxy.

Mono-(C₁-C₆)- and mono-(C₁-C₄)-alkylamino are a straight-chain orbranched monoalkylamino radical having respectively 1 to 6 and 1 to 4carbon atoms. Preference is given to a straight-chain or branchedalkylamino radical having 1 to 4, particularly preferably having 1 to 3,carbon atoms. Preferred examples which may be mentioned are:methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino,n-pentylamino and n-hexylamino.

Di-(C₁-C₆)- and di-(C₁-C₄)alkylamino are a straight-chain or brancheddialkylamino radical, where the alkyl radicals may be identical ordifferent and each respectively contains 1 to 6 and 1 to 4 carbon atoms.Preference is given to a straight-chain or branched dialkylamino radicalin which the alkyl radicals each contain 1 to 4, particularly preferably1 to 3, carbon atoms. Preferred examples which may be mentioned are:dimethylamino, diethylamino, di-n-propylamino, diisopropylamino,di-tert-butylamino, di-n-pentylamino, di-n-hexylamino, ethylmethylamino,isopropyl-methylamino, n-butylmethylamino, tert-butylmethylamino,n-hexylisopentylamino.

(C₁-C₆)- and (C₁-C₄)-alkoxycarbonyl is a straight-chain or branchedalkoxycarbonyl radical having respectively 1 to 6 and 1 to 4 carbonatoms in the alkoxy group. Preferred examples which may be mentionedare: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl and tert-butoxycarbonyl.

(C₁-C₆)- and (C₁-C₄)-alkylsulfonyl is a straight-chain or branchedalkylsulfonyl radical having respectively 1 to 6 and 1 to 4 carbon atomsin the alkyl group. Preferred examples which may be mentioned are:methylsulfonyl, ethylsulfonyl, n-propyl-sulfonyl, isopropylsulfonyl andtert-butylsulfonyl.

(C₁-C₆)-acyloxy is a straight-chain or branched alkyl radical which has1 to 6 carbon atoms and which has in position 1 a doubly bonded oxygenatom and is linked in position 1 via a further oxygen atom. Preferredexamples which may be mentioned are: acetoxy, propionoxy, n-butyroxy,i-butyroxy, pivaloyloxy, n-hexanoyloxy.

(C₁-C₆)- and (C₁-C₄)-acylamino is an amino group having a straight-chainor branched alkanoyl substituent which has respectively 1 to 6 and 1 to4 carbon atoms and is linked via the carbonyl group. Preferred exampleswhich may be mentioned are: formamido, acetamido, propionamido,n-butyramido and pivaloylamido.

(C₁-C₆)-alkylaminocarbonyl is an amino group which is linked via acarbonyl group and which has a straight-chain or branched alkylsubstituent having 1 to 6 carbon atoms. An alkylaminocarbonyl radicalhaving 1 to 4 carbon atoms is preferred. Preferred examples which may bementioned are: methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylaminocarbonyl and t-butyl-aminocarbonyl.

(C¹-C₄)-alkoxycarbonylamino is an amino group having a straight-chain orbranched alkoxycarbonyl substituent which has 1 to 4 carbon atoms in thealkoxy radical and is linked via the carbonyl group to the amino group.Preferred examples which may be mentioned are: methoxycarbonylamino,ethoxycarbonylamino, n-propoxycarbonyl-amino, isopropoxycarbonylaminoand t-butoxycarbonylamino.

Mono- and di-[(C₁-C₆)-alkylsulfonyl]amino is an amino group havingrespectively one and two identical or different, straight-chain orbranched alkylsulfonyl substituents each having 1 to 6 carbon atoms inthe alkyl group. Preferred examples which may be mentioned are:methylsulfonylamino, bis-(methylsulfonyl)amino, ethylsulfonylamino,n-propylsulfonylamino, isopropylsulfonylamino andtert-butylsulfonylamino.

(C₆-C₁₀)-aryl is an aromatic radical having 6 to 10 carbon atoms.Preferred aryl radicals are phenyl and naphthyl.

(C₃-C₈)-cycloalkyl is a cycloalkyl group having 3 to 8 carbon atoms. Acycloalkyl group having 3 to 6 carbon atoms is preferred. Preferredexamples which may be mentioned are: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cyclopropyl,cyclopentyl and cyclohexyl are particularly preferred.

(C₃-C₈)-cycloalkylcarbonyl is a cycloalkyl group as defined above whichis linked via a carbonyl group. Cyclopropylcarbonyl is preferred.

5- or 6-membered heteroaryl is a heteroaromatic radical havingrespectively 1 to 3 or 1 to 2 ring nitrogen atoms which is linked via aring carbon atom or, where appropriate, via a ring nitrogen atom.Preferred examples which may be mentioned are: pyrrolyl, imidazolyl,pyrazolyl, triazolyl, pyridyl, pyrimidinyl and pyridazinyl.

5- or 6-membered heterocyclyl having up to two heteroatoms from theseries N, O and/or S is a saturated heterocycle. Preferred exampleswhich may be mentioned are: pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl and piperidinyl. Piperazinyl is preferred.

5- to 7-membered, saturated or partially unsaturated heterocyclyl whichis linked via a ring nitrogen atom is a nonaromatic heterocycle which,besides the nitrogen atom, may comprise a further heteroatom from theseries N, O, S, SO or SO₂ and, where appropriate, one or two doublebonds. A 5- to 6-membered. saturated heterocycle which, besides thenitrogen atom, may comprise a further heteroatom from the series N, O orS is preferred. Preferred examples which may be mentioned are:pyrrolidinyl, pyrrolinyl, piperdinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl,hexahydroazepinyl and hexahydro-1,4-diazepinyl. Piperidinyl,piperazinyl, morpholinyl and pyrrolidinyl.

Halogen is fluorine, chlorine, bromine and iodine. Fluorine, chlorineand bromine are preferred. Fluorine and chlorine are particularlypreferred.

Preferred compounds of the formula (I) are those in which

-   R¹ is a group of the formula    in which    -   A is CR⁴R⁵, O, S, NR⁶ or —CH₂NR⁶—, where    -   R⁴ and R⁵ are independently of one another hydrogen,        (C₁-C₄)-alkyl, which may be substituted by hydroxy, or hydroxy,        fluorine, carboxyl or (C₁-C₄)-alkoxycarbonyl, or together with        the carbon atom to which they are bonded form a carbonyl group,        and    -   R⁶ is hydrogen, (C₂-C₄)-alkenyl, (C₃-C₆)-cycloalkyl,        (C₁-C₄)-alkoxycarbonyl, formyl, acetyl,        (C₃-C₆)-cycloalkylcarbonyl, (C₁-C₄)-alkylsulfonyl,        aminocarbonyl, (C₁-C₄)-alkylamino-carbonyl or is (C₁-C₄)-alkyl        which in turn may be substituted by hydroxy, methoxy, ethoxy,        (C₁-C₄)-alkoxycarbonyl, amino, dimethylamino, diethylamino,        pyrrolidino, piperidino or morpholino,        or-   R¹ is 5-membered heteroaryl which is linked via a ring nitrogen atom    and has up to two further ring nitrogen atoms and which may be    substituted once or twice, identically or differently, by fluorine,    chlorine, (C₁-C₄)-alkoxycarbonyl or (C₁-C₄)-alkyl which in turn is    optionally substituted by hydroxy,-   R² is phenyl which may be substituted once or twice, identically or    differently, by substituents selected from the group of fluorine,    chlorine, cyano, (C₁-C₄)-alkyl, trifluoromethyl, formyl, acetyl,    (C₁-C₄)-alkoxy, hydroxy, acetoxy, pivaloyloxy, amino, formylamino,    acetylamino and methylsulfonylamino,    -   where (C₁-C₄)-alkyl and (C₁-C₄)-alkoxy in turn may each be        substituted by hydroxy, amino, methoxy, ethoxy or acetylamino,        or-   R² is pyrrolyl, pyridyl or pyrimidinyl, each of which may be    substituted by amino, fluorine, chlorine, methyl, ethyl, methoxy or    ethoxy,    and-   R³ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl,    trifluoromethyl, nitro or cyano.

Particularly important compounds of the formula (I) are those in which

-   R¹ is an imidazolyl which is attached via a ring nitrogen atom or is    a piperazinyl which is attached via a ring nitrogen atom and which    may be substituted on the second ring nitrogen atom by methyl,    ethyl, 2-hydroxyethyl, 2-methoxy-ethyl, acetyl, tert-butoxycarbonyl,    cyclopropylcarbonyl, aminocarbonyl or methylsulfonyl.

Likewise particularly important compounds of the formula (I) are thosein which

-   R² is phenyl which may be substituted by hydroxy or fluorine or is    pyridyl.

Very particularly preferred compounds of the formula (I) are those inwhich

-   R¹ is imidazolyl which is attached via a ring nitrogen atom or is    piperazinyl which is attached via a ring nitrogen atom and which may    be substituted on the second ring nitrogen atom by methyl, ethyl,    2-hydroxyethyl, 2-methoxyethyl, acetyl, tert-butoxycarbonyl or    methylsulfonyl,-   R² is phenyl which may be substituted by fluorine or hydroxy in    position 4 relative to the linkage point on the phenyl ring,    and-   R³ is located in position 4 relative to the linkage point of the    pyridazinone ring and is hydrogen, fluorine, chlorine, methyl or    trifluoromethyl.

Especially preferred compounds of the formula (I) are selected from thegroup of the following compounds:

The invention further relates to a process for preparing the compoundsof the formula (I), characterized in that compounds of the formula (II)

in which

-   R³ has the meaning indicated above, and-   X¹ and X² are each halogen, preferably bromine or chlorine,    are first converted with a compound of the formula (III)    R¹—H  (III),    in which R¹ has the meaning indicated above    in an inert solvent, where appropriate in the presence of an    auxiliary base and/or of an alkali metal iodide, into compounds of    the formula (IV)    in which R¹, R³ and X² each have the abovementioned meaning,    and the latter are then reacted with a compound of the formula (V)    in which R² has the meaning indicated above,    in an inert solvent in the presence of a base and, where    appropriate, in the presence of an alkali metal iodide.

Inert solvents for both process steps are, for example, alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol orethylene glycol mono-methyl ether, ethers such as diethyl ether, methyltert-butyl ether, dioxane, tetra-hydrofuran, ethylene glycol dimethylether or diethylene glycol dimethyl ether, or dipolar aprotic solventssuch as dimethylformamide, dimethylacetamide, dimethyl sulfoxide,sulfolane or N-methylpyrrolidone. Dimethylformamide orn-methyl-pyrrolidone is preferred.

Both process steps can also where appropriate be carried out withoutsolvent, i.e. undiluted or in the melt.

Examples of suitable auxiliary bases for process step (II)+(III)→(IV)are alkali metal or alkaline earth metal carbonates such as sodium,potassium, cesium or calcium carbonate, or tertiary organic amines suchas triethylamine, diisopropyl-ethylamine, N-methylmorpholine,N-methylpiperidine or 1,4-diazabicyclo-[2.2.2]octane. Tertiary aminesare preferred. The auxiliary base is in this case employed in a molarratio of from 0.75:1 to 2:1 based on the compound (II); a molar ratio offrom 0.95:1 to 1.5:1 is preferred.

Bases suitable for process step (IV)+(V)→(I) are alkali metal oralkaline earth metal carbonates such as sodium, potassium or calciumcarbonate, alkali metal alcoholates such as sodium or potassiummethanolate, sodium or potassium ethanolate or potassium tert-butoxide,alkali metal hydrides such as sodium or potassium hydride, amides suchas sodamide, lithium bis(trimethylsilyl)amide or lithiumdiisopropylamide, tertiary organic amines such as triethylamine,ethyl-diisopropylamine, N-methylmorpholine, N-methylpiperidine or1,4-diaza-bicyclo[2.2.2]octane, or organometallic compounds such asn-butyllithium. 1,4-Diazabicyclo[2.2.2]octane; sodium hydride, potassiumhydride or potassium tert-butoxide is preferred. The base is in thiscase employed in a molar ratio of from 0.75:1 to 2:1 based on thecompound (V); a molar ratio of from 0.95:1 to 1.5:1 is preferred.

Both process steps can be carried out in the presence of alkali metaliodides such as lithium, sodium, potassium or cesium iodide. The iodidein this case is employed in a molar ratio of from 0.001:1 to 2:1 basedon the compound (II) or (IV); a molar ratio of from 0.01:1 to 1:1 ispreferred.

The compounds (II) and (III) are employed in a molar ratio of from 1:1to 1:10, preferably of from 1:1 to 1:5. The reaction is carried out in atemperature range from +20° C. to +200° C., preferably from +20° C. to+120° C. The reaction can be carried out under atmospheric pressure,under reduced or under elevated pressure; it is preferably carried outunder atmospheric pressure.

The compounds (IV) and (V) are employed in a molar ratio of from 10:1 to1:10, preferably from 1:1 to 1:3. The reaction is carried out in atemperature range from +20° C. to +200° C., preferably from +100° C. to+180° C. The reaction can be carried out under atmospheric pressure,under reduced or under elevated pressure; it is preferably carried outunder atmospheric pressure.

The compounds of the formula (II) are known or can be prepared inanalogy to processes known from the literature [see, for example, Drury,Angew. Chemie 77, 282 (1965)].

The compounds of the formulae (III) and (V) are commercially available,known from the literature or can be prepared in analogy to processesknown from the literature.

In one variant of the process, the compounds of the formula (I) can alsobe obtained by either

-   [A] Reacting compounds of the formula (VI)    in which    -   R^(1*) has the meaning indicated above for R¹, but is not in        turn substituted by bromine or iodine,    -   R^(3*) has the meaning indicated above for R³, but is not        bromine or iodine, and    -   Y is bromine, iodine or trifluoromethylsulfonyloxy (triflate),        in a coupling reaction with a compound of the formula (VII)        in which    -   R^(2*) has the meaning indicated above for R², but is not in        turn substituted by bromine or iodine, and    -   R⁷ is hydrogen or methyl, or the two radicals together form a        CH₂CH₂ or C(CH₃)₂—C(CH₃)₂ bridge,        in an inert solvent in the presence of a suitable palladium        catalyst and of a base,        or-   [B] Reacting compounds of the formula (VIII)    in which    -   R^(1*), R^(3*) and R⁷ each have the meaning indicated above,        in a coupling reaction with a compound of the formula (IX)        R²-Z  (IX),        in which    -   R² has the meaning indicated above, and    -   Z is bromine or iodine,        in an inert solvent in the presence of a suitable palladium        catalyst and of a base.

Examples of suitable inert solvents for variant [A] of the process arealcohols such as methanol, ethanol, n-propanol, isopropanol orn-butanol, aromatic hydrocarbons such as benzene, xylene or toluene, ordipolar aprotic solvents, such as dimethylformamide, dimethylacetamide,dimethyl sulfoxide, sulfolane or n-methylpyrrolidone. It is likewisepossible to employ mixtures of said solvents. Dimethylformamide or amixture of ethanol and toluene is preferred.

Examples of inert solvents suitable for variant [B] of the process aredipolar aprotic solvents such as dimethylformamide, dimethylacetamide,dimethyl sulfoxide, sulfolane or N-methylpyrrolidone. Dimethyl sulfoxideis preferred.

Palladium catalysts suitable for both variants of the process are thepalladium(0) and palladium(II) complex compounds usual for Suzukicouplings; palladium tetrakis-triphenylphosphane,[1,1-bis(diphenylphosphino)-ferrocenyl]dichloropalladium(II) complex orbistriphenylphosphane dichloropalladium(II) complex is preferred. Thepalladium compound is in this case employed in a molar ratio of from0.005:1 to 0.5:1, preferably in a molar ratio of from 0.02:1 to 0.15:1,based on the compound (VI) or (VIII).

Bases suitable for both variants of the process are aqueous solutions ofalkali metal carbonates and bicarbonates and of alkali metal salts ofacetic or propionic acid; sodium carbonate is preferred. Based on thecompound (VI) or (VIII), a molar ratio of from 1:1 to 10:1, preferablyof from 1.5:1 to 8:1, of the base is used.

The compounds (VI) and (VII) are employed in a molar ratio of from 3:1to 1:3, preferably of from 1.2:1 to 1:1.2. The reaction is carried outin a temperature range from +20° C. to +150° C., preferably from +50° C.to +100° C. The reaction can be carried out under atmospheric pressure,under reduced or under elevated pressure; it is preferably carried outunder atmospheric pressure.

The compounds (VIII) and (IX) are employed in a molar ratio of from 2:1to 1:10, preferably from 1:1 to 1:3. The reaction is carried out in atemperature range from +20° C. to +150° C., preferably from +50° C. to+100° C. The reaction can be carried out under atmospheric pressure,under reduced or under elevated pressure; it is preferably carried outunder atmospheric pressure.

The compounds of the formula (VI) and (VIII) can be prepared inaccordance with the previously described process (IV)+(V)→(I).

The compounds of the formula (VIII) can also be obtained in analogy tovariant [A] of the process by palladium-catalyzed reaction of compoundsof the formula (VI) with appropriate boric acid derivatives such as, forexample, 4,4,4′,4′,5,5,5′,5′-octa-methyl-2,2′-bi-1,3,2-dioxaborolane[cf., for example, A. Suzuki, Acc. Chem. Res, 15, 178 (1982); Miyaura etal., J. Am. Chem. Soc., 111, 314 (1989)].

The compounds of the formula (VII) are commercially available, knownfrom the literature or can be prepared in analogy to processes knownfrom the literature [see, for example, A. Suzuki, in: Metal-catalyzedcross-coupling reactions, F. Driedrich and P. J. Stang, editors, Wiley,Weinheim 1998].

The compounds of the formula (IX) are commercially available, known fromthe literature or can be prepared in analogy to processes known from theliterature.

In a further variant of the process, the compounds of the formula (I)can also be prepared by first converting compounds of the formula (II)with a compound of the formula (V) in an inert solvent in the presenceof a base into compounds of the formula (X)

in which R², R³ and X¹ each have the meaning indicated above,and then reacting the latter with a compound of the formula (III) in aninert solvent, where appropriate in the presence of an auxiliary baseand/or of an alkali metal iodide.

Inert solvents for process step (II)+(V)→(X) are advantageously etherssuch as methyl tert-butyl ether, dioxane, tetrahydrofuran or ethyleneglycol dimethyl ether. Dioxane is preferred.

Examples of inert solvents for process step (X)+(III)→(I) are etherssuch as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether ordiethylene glycol dimethyl ether, or dipolar aprotic solvents such asdimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane orN-methylpyrrolidone. Dimethylformamide is preferred. This process stepcan also where appropriate be carried out without solvent, i.e.undiluted or in the melt.

Examples of bases suitable for process step (II)+(V)→(X) are metalalcoholates such as sodium or potassium methanolate, sodium or potassiumethanolate, thallium methanolate or ethanolate or potassiumtert-butoxide, metal hydrides such as sodium, potassium or lithiumhydride, amides such as sodium or potassium amide, lithium or sodiumbis(trimethylsilyl)amide or lithiumdiisopropylamide, or organometalliccompounds such as methyl-, n-butyl- or phenyllithium. Sodium hydride ispreferred. The base is in this case employed in a molar ratio of from1.5:1 to 1:1.5, based on the compound (V); a molar ratio of from 1:1 to1.1:1 is preferred. Reaction of the base with the compound (V) iscarried out in a temperature range from −78° C. to +30° C.; on use ofsodium hydride, this preferably takes place in a temperature range from0° C. to +30° C.

Auxiliary bases suitable for process step (X)+(III)→(I) are alkali metalor alkaline earth metal carbonates such as sodium, potassium, cesium orcalcium carbonate, or tertiary organic amines such as triethylamine,ethyldiisopropylamine, N-methyl-morpholine or N-methylpiperidine;triethylamine or ethyldiisopropylamine is preferred. The base isemployed in this case in a molar ratio of from 1:1 to 2:1 based on thecompound (X), a molar ratio of from 1:1 to 1.5:1 is preferred.

Process step (X)+(III)→(I) can advantageously be carried out in thepresence of alkali metal iodides such as lithium, sodium, potassium orcesium iodides; sodium or potassium iodide is preferred. The iodide isemployed in this case in a molar ratio of from 0.1:1 to 2:1 based on thecompound (X); a molar ratio of 1:1 is preferred.

The compounds (II) and (V) are employed in a molar ratio of from 0.5:1to 2:1, preferably of 1:1. The reaction is carried out in a temperaturerange from 0° C. to +100° C., preferably from +10° C. to +30° C. Thereaction can be carried out under atmospheric pressure, under reduced orunder elevated pressure; it is preferably carried out under atmosphericpressure.

The compounds (III) and (X) are employed in a molar ratio of from 1:3 to5:1, preferably from 1:1.5 to 2:1. The reaction is carried out in atemperature range from +50° C. to +200° C., preferably from +120° C. to+170° C. The reaction can be carried out under atmospheric pressure,under reduced or under elevated pressure; it is preferably carried outunder atmospheric pressure.

In a further variant of the process, the compounds of the formula (I)can also be prepared by first converting compounds of the formula (II)with an excess of compound (V) in an inert solvent in the presence of abase and, where appropriate, in the presence of an alkali metal iodideinto compounds of the formula (XI)

in which R² and R ³ each have the meaning indicated above,and then reacting the latter with a compound of the formula (III) in aninert solvent, where appropriate in the presence of an auxiliary baseand/or of an alkali metal iodide.

Inert solvents for process step (II)+(V)→(XI) are advantageously aproticsolvents such as, for example, dimethylformamide, dimethylacetamide,dimethylsulfoxide or sulfolane or ethers such as methyl tert-butylether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether.Dimethylformamide is preferred.

Examples of inert solvents for process step (XI)+(III)→(I) are etherssuch as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether ordiethylene glycol dimethyl ether, or dipolar aprotic solvents such asdimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane orN-methylpyrrolidone. Dimethyl-formamide is preferred. This process stepcan also where appropriate be carried out without solvent, i.e.undiluted or in the melt.

Examples of suitable bases for process step (II)+(V)→(XI) are metalalcoholates such as sodium or potassium methanolate, sodium or potassiumethanolate, thallium methanolate or ethanolate or potassiumtert-butoxide, metal hydrides such as sodium, potassium or lithiumhydride, amides such as sodium or potassium amide, lithium or sodiumbis(trimethylsilyl)amide or lithium diisopropylamide, or organometalliccompounds such as methyl-, n-butyl- or phenyllithium. Sodium hydride ispreferred. The base is employed in this case in a molar ratio of from1.5:1 to 1:1.5 based on the compound (V); a molar ratio of from 1:1 to1.1:1 is preferred. Reaction of the base with the compound (V) iscarried out in a temperature range from −78° C. to +30° C.; on use ofsodium hydride, this preferably takes place in a temperature range from0° C. to +30° C.

Auxiliary bases suitable for process step (XI)+(III)→(I) are alkalimetal or alkaline earth metal carbonates such as sodium, potassium,cesium or calcium carbonate or tertiary organic amines such astriethylamine, ethyldiisopropylamine, N-methyl-morpholine,N-methylpiperidine or 1,4-diazabicyclo[2.2.2]octane;1,4-diaza-bicyclo[2.2.2]octane or ethyldiisopropylamine is preferred.The base is employed in this case in a molar ratio of from 0.75:1 to 2:1based on the compound (III); a molar ratio of from 0.95:1 to 1.5:1 ispreferred.

Process step (II)+(V)→(XI) can advantageously be carried out in thepresence of alkali metal iodides such as lithium, sodium, potassium orcesium iodide; sodium or potassium iodide is preferred. The iodide is inthis case employed in a molar ratio of from 0.05:1 to 2:1 based on thecompound (V); a molar ratio of from 0.1:1 to 0.5:1 is preferred.

Process step (XI)+(III)→(I) can likewise advantageously be carried outin the presence of alkali metal iodides such as lithium, sodium,potassium or cesium iodide; sodium or potassium iodide is preferred. Theiodide is in this case employed in a molar ratio of from 0.1:1 to 2:1based on the compound (XI); a molar ratio of 1:1 is preferred.

The compounds (II) and (V) are employed in a molar ratio of from 0.05:1to 0.5:1, preferably of from 0.1:1 to 0.5:1. The reaction is carried outin a temperature range from +50° C. to +200° C., preferably from +100°C. to +160° C. The reaction can be carried out under atmosphericpressure, under reduced or under elevated pressure; it is preferablycarried out under atmospheric pressure.

The compounds (III) and (XI) are employed in a molar ratio of from 1:1to 5:1, preferably of from 1:1 to 2:1. The reaction is carried out in atemperature range from +50° C. to +200° C., preferably from +100° C. to+170° C. The reaction can be carried out under atmospheric pressure,under reduced or under elevated pressure; it is preferably carried outunder atmospheric pressure.

Compounds of the formula (I), in which R¹ is optionally substituted1,2,3-triazol-1-yl can also be prepared by first converting compounds ofthe formula,(X) with a metal azide in an inert solvent into compounds ofthe formula (XII)

in which R² and R³ each have the meaning indicated above,and then reacting the latter with a compound of the formula (XIII)R⁸—C≡C—R⁹  (XIII),in which

-   R⁸ and R⁹ are independently of one another hydrogen,    (C₁-C₆)-alkoxycarbonyl or are (C₁-C₆)-alkyl which may in turn be    substituted by hydroxy or halogen,    in the presence or in the absence of an inert solvent to give    compounds of the formula (XIVa) or (XIVb)    in which R², R³, R⁸ and R⁹ each have the meaning indicated above.

Examples of inert solvents for process step (X)→(XII) are advantageouslyaprotic solvents such as, for example, dimethylformamide,dimethylacetamide, dimethyl sulfoxide, sulfolane, acetone, acetonitrileor ethers such as dioxane, tetrahydrofuran or ethylene glycol dimethylether. Dimethylformamide is preferred.

Examples of inert solvents for process step (XII)+(XIII)→(XIVa) or(XIVb) are ethers such as dioxane, tetrahydrofuran, ethylene glycoldimethyl ether or diethylene glycol dimethyl ether, dipolar aproticsolvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane or N-methylpyrrolidone, or aromatic hydrocarbonssuch as benzene, toluene or isomeric xylenes, or chlorobenzene ornitrobenzene. This process step can also where appropriate be carriedout without solvent. The reaction is preferably carried out in tolueneor without solvent.

The compounds (X) are reacted with the azide in a molar ratio of from1:1 to 1:15, preferably of from 1:2 to 1:6. The azides used are alkalimetal salts of hydrazoic acid; sodium azide is preferred. The reactionis carried out in a temperature range from +20° C. to +80° C.,preferably from +40° C. to +60° C. The reaction can be carried out underatmospheric pressure, under reduced or under elevated pressure; it ispreferably carried out under atmospheric pressure.

The compounds (XII) and (XIII) are employed in a molar ratio of from 1:1to 1:15, preferably of from 1:2 to 1:8. The reaction is carried out in atemperature range from +20° C. to +130° C., preferably from +80° C. to+120° C. The reaction can be carried out under atmospheric pressure,under reduced or under elevated pressure; it is preferably carried outunder atmospheric pressure.

The compounds of the formula (XIII) are commercially available, knownfrom the literature or can be prepared in analogy to processes knownfrom the literature.

The compounds of the formula (I) surprisingly showed a valuable range ofpharmacological effects which could not have been predicted and aretherefore suitable in particular for the prophylaxis and/or treatment ofdisorders in humans and animals.

The pharmaceutical activity of the compounds of the formula (I), inparticular their antifibrotic effect, can be explained by their effectas lysyl oxidase inhibitors.

The compounds of the invention are, because of their pharmacologicalproperties suitable alone or in combination with one or more otheractive ingredients for the prophylaxis and/or treatment of disorders inhumans and warm-blooded species, in particular of disorderscharacterized by harmful buildup of collagen and/or by excessive lysyloxidase enzymatic activity; irrespective of the disorder underlying thisdamage.

Detrimental basic disorders in this sense may be radiation damage, i.e.following radiotherapy, damage resulting from chemotherapy, e.g. withbleomycin or Adriamycin, viral disorders, e.g. hepatitis B infection,chronic intoxications such as, for example, alcohol abuse, parasiticdisorders such as, for example, schistosomiasis, congenital disorderssuch as, for example, Wilson's syndrome, metabolic disorders such as,for example, diabetes, autoimmune diseases or else disorders of unknownorigin. It is common to all of them that they induce fibrotic damage inone or more organs. Therapy with the compounds of the invention controlsthe fibrotic damage and the sequelae associated therewith, such as, forexample, organ failure, varicosis, portal hypertension, formation ofmalignant tumors.

The therapeutic use of the compounds of the invention likewise includesthe prophylaxis and/or treatment of fibrotic disorders of the internalorgans. Examples which may be mentioned here are the lung, heart,kidney, bone marrow and, in literature or can be prepared in analogy toprocesses known from the literature.

The compounds of the formula (I) surprisingly showed a valuable range ofpharmacological effects which could not have been predicted and aretherefore suitable in particular for the prophylaxis and/or treatment ofdisorders in humans and animals.

The pharmaceutical activity of the compounds of the formula (I), inparticular their antifibrotic effect, can be explained by their effectas lysyl oxidase inhibitors.

The compounds of the invention are, because of their pharmacologicalproperties suitable alone or in combination with one or more otheractive ingredients for the prophylaxis and/or treatment of disorders inhumans and warm-blooded species, in particular of disorderscharacterized by harmful buildup of collagen and/or by excessive lysyloxidase enzymatic activity; irrespective of the disorder underlying thisdamage.

Detrimental basic disorders in this sense may be radiation damage, i.e.following radiotherapy, damage resulting from chemotherapy, e.g. withbleomycin or Adriamycin, viral disorders, e.g. hepatitis B infection,chronic intoxications such as, for example, alcohol abuse, parasiticdisorders such as, for example, schistosomiasis, congenital disorderssuch as, for example, Wilson's syndrome, metabolic disorders such as,for example, diabetes, autoimmune diseases or else disorders of unknownorigin. It is common to all of them that they induce fibrotic damage inone or more organs. Therapy with the compounds of the invention controlsthe fibrotic damage and the sequelae associated therewith, such as, forexample, organ failure, varicosis, portal hypertension, formation ofmalignant tumors.

The therapeutic use of the compounds of the invention likewise includesthe prophylaxis and/or treatment of fibrotic disorders of the internalorgans. Examples which may be mentioned here are the lung, heart,kidney, bone marrow and, in particular, liver. The compounds of theinvention can therefore be used to treat for example hepatic fibrosis,cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis,cardiomyopathy, nephropathy, glomerulonephritis, interstitial renalfibrosis, fibrotic damage resulting from diabetes, myelofibrosis andsimilar fibrotic disorders.

In a further aspect of the invention, dermatological fibroses aretreated by compounds of the formula (I). Examples of such disorderswhich may be mentioned are scleroderma, morphea; keloids, hypertrophicscarring (also following surgical procedures) and naevi. The compoundsof the invention an also be employed for aging and keratinizing skin.

It is also possible with the compounds of the invention to treatfibrotic disorders of the eye such as diabetic retinopathy andproliferative vitroretinopathy; they can also be employed advantageouslyfor controlling postoperative scarring, e.g. following glaucomaoperations.

The compounds of the invention can additionally be employedtherapeutically in the control of neoplastic disorders, especially thosedisorders characterized by metastasis associated with neoangiogenesis.

The present invention also relates to the use of the compounds of theformula (I) for producing medicaments for the prophylaxis and/ortreatment of the aforementioned pathological states.

The present invention further relates to a method for the prophylaxisand/or treatment of the aforementioned pathological states using thecompounds of the formula (I).

The present invention further relates to medicaments which comprise atleast one compound of the formula (I), preferably together with one ormore pharmacologically acceptable excipients or carriers, and to the usethereof for the aforementioned purposes.

The active ingredients can be converted in a known manner into the usualformulations such as tablets, coated tablets, pills, granules, aerosols,syrups, creams, emulsions, suspension and solutions, using inert,nontoxic pharmaceutically suitable carriers and solvents. In each ofthese cases, the therapeutically active compound is to be present in aconcentration of about 0.01 to 90% by weight of the complete mixture,i.e. in amounts sufficient to reach the indicated dosage range.

The formulations are produced for example by extending the activeingredients with solvents and/or carriers, where appropriate usingemulsifiers and/or dispersants, it being possible where appropriate, forexample when water is used as diluent, to use organic solvents asauxiliary solvents.

Administration takes place in a conventional way, preferably orally,parenterally or topically.

In the case of parenteral administration, solutions of the activeingredients can be employed using suitable liquid carrier materials.

It has generally proved advantageous on intravenous administration toadminister amounts of about 0.001 to 20 mg/kg, preferably about 0.01 to10 mg/kg, of bodyweight to achieve effective results, and on oraladministration the dosage is about 0.01 to 60 mg/kg, preferably 0.1 to30 mg/kg, of bodyweight.

In may nevertheless be necessary to deviate from the stated amounts, inparticular as a function of bodyweight and the nature of theadministration route, on the individual response towards the medicament,the nature of its formulation and the time or interval over whichadministration takes place. Thus, it may in some cases be sufficient tomake do with less than the aforementioned minimum amount, whereas inother cases the stated upper limit must be exceeded. Where largeramounts are administered, it may be advisable to divide them into aplurality of single doses over the day.

The present invention is illustrated by the following, non-restrictive,preferred examples which, however, by no means limit the invention.

The percentage data in the following tests and examples are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data for liquid/liquidmixtures are in each case based on volume.

A. Assessment of the Physiological Activity

The following biological assays can be used to investigate the in vitroand in vivo effects of the compounds of the invention:

1. Test for Lysyl Oxidase-Inhibitory Effect:

The enzyme was isolated from bovine aortas in a modification of a methodof Kagan et al. [Biochem. J. 177, 203-214 (1979)] by extraction withphosphate buffer containing urea, followed by precipitation andchromatography on DEAE-Sephadex.

The test solution (total volume 200 μl) is composed of 1.5 mMhomovanillinic acid, 5 mM 1,5-diaminopentane, 1 unit of horseradishperoxidase and 1.5 M urea in 50 mM sodium borate buffer of pH 8.2. Theenzyme was preincubated with the compound to be tested for 15 minutes;the reaction was started by adding diaminopentane andhomovanillin/horseradish peroxidase. The fluorescence of thehomovanillin dimer which formed was measured with excitation at 315 nmand emission at 425 nm. This test arrangement is a modification of themethod of Trackman et al. [Anal. Biochem. 113, 336-341 (1981)].

The IC₅₀ as a measure of the inhibition of lysyl oxidase is found bytesting various concentrations of substance and using theconcentration-effect plots. Examples of IC₅₀ values for the compounds ofthe invention are listed in Table 1 below: TABLE 1 IC₅₀ (μM) Comparativecompounds: β-Aminopropionitrile (BAPN) 104-Ethoxy-2-methyl-5-morpholino-3(2H)- >4 pyridazinone (emorfazone)Exemplary embodiments: Ex. 5 0.017 Ex. 8 0.007 Ex. 82 0.011 Ex. 12 0.003Ex. 25 0.005 Ex. 34 0.009 Ex. 81 0.007 Ex. 176 0.010

The compounds of the invention show a distinctly stronger enzymeinhibitory effect on lysyl oxidase than does the reference compound BAPNor 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (emorfazone) whichcorresponds to the structurally closest prior art.

2. Test of Antifibrotic Effect in the Liver

2.1 Animal Models:

a) Model of Chronic Carbon Tetrachloride Intoxication:

Chronic carbon tetrachloride (CCl₄) treatment is a standard method forgenerating hepatic fibrosis of nonviral origin and subsequent cirrhosis.It is generally accepted as a model of hepatic fibrosis and cirrhosis inhumans [E. McLean, A. McLean, P. Sutton, Instant Fibrosis: An improvedmethod for producing cirrhosis of the liver in rats by simultaneousadministration of carbon tetrachloride and phenobarbitone, Br. J. Exp.Pathol. 50 502-506 (1969)].

Female Sprague-Dawley rats (200-220 g) were employed. In order toachieve maximum microsomal metabolization of the CCl₄, the animalsreceived isoniazid in the drinking water (1 g/l) for one week beforestarting the administration of carbon tetrachloride. CCl₄ wasadministered orally each fifth day in a dose of 0.2 ml/100 g ofbodyweight in a 1:1 mixture with mineral oil. The compounds of theinvention were given orally in the same period, as indicated in Table 3,preferably in Solutol®/ethanol/PBS mixtures. Necropsy was performed 6weeks after starting the treatment.

b) Model of Bile Duct Ligature:

The experiments were carried out with female Sprague-Dawley rats(200-220 g). In order to generate chronic fibrosis, the bile duct(common hepatic duct) was doubly ligated in a surgical procedure.Ethibloc® occlusion emulsion (Ethicon, Norderstedt, Germany), a mixtureof prolamine and ethanol, was instilled retrogradely into the biliarysystem [J. Kountouras, B. Billing, P. Scheuer, Prolonged bileobstruction: A new experimental model for cirrhosis in the rat, Br. J.Exp. Pathol. 6, 305-311 (1984); G. Boigk, L. Stroedter, H. Herbst, J.Waldschmidt, E. O. Riecken, D. Schuppan, Silymarin retards collagenaccumulation in early and advanced biliary fibrosis secondary tocomplete bile duct obliteration in rats, Hepatology 26, 643-649 (1997)].The compounds of the invention were given orally in the same period, asindicated in Table 2, preferably in Solutol®/ethanol/PBS mixtures. Theanimals were sacrificed and investigated three weeks after the surgicalprocedure.

c) Model of Serum-Induced Hepatic Fibrosis:

A septal fibrosis can be induced in rats also by repeated injection ofheterologous serum. For this purpose, 0.5 ml of sterile-filtered porcineserum is administered i.p. to each animal twice a week [Bhunchet andWake, Hepatology 16, 1452-73 (1992)].

The experiments were carried out with female Sprague-Dawley rats(200-220 g). After 6-8 weeks, the septal fibrosis is histologicallymanifest and can also be detected through an increase in the liverhydroxyproline content.

2.2 Evaluation of the Animal Models:

a) Histological Assessments/Morphometry:

Standardized transverse cylinders of liver tissue (approx. 10×2 mm) werecut out of the right anterior lobe of each rat liver. Frozen sectionswere stained with 0.1% picrosirius red solution to detect scar collagenassociated with hepatic fibrosis. The contrast was increased bycounterstaining with fast green. The extent of hepatic fibrosis wasfound as a percentage of the part stainable with picrosirius red in eachsection. A Leica Quantimed 500 MC system (Leica, Germany) was used forautomatic morphometry. In this case, the color detection parameters werestandardized and left constant during an experiment. 64 viewing fieldswhich by means of a standard reticle which covers 31 mm² were employedwith 100× magnification for the evaluation.

b) Collagen Content:

The total collagen content was estimated by means of the tissue4-hydroxyproline concentration. The method of Prockop and Udenfried [D.J. Prockop and S. Udenfried, A specific method for the analysis ofhydroxyproline in tissues and urine, Anal. Biochem. 1, 228-239 (1960)]in modified form was used: liver samples with a wet weight of 60-90 mgwere dried and then hydrolyzed in 6 N hydrochloric acid at 100° C. for17 hours. The hydrolyzate was dried by evaporation and reconstituted in5 ml of deionized water. 200 μl of this hydrolyzate were mixed with 200μl of ethanol and oxidized with 200 μl of a 0.7% strength solution ofchloramine T in citrate buffer (5.7 g of sodium acetate, 3.75 g oftrisodium citrate, 0.55 g of citric acid, 38.5 ml of ethanol, made up to100 ml with water) at room temperature for 20 minutes. Then, 400 μl ofEhrlich's reagent (12 g of p-dimethylaminobenzaldehyde and 2.7 g ofsulfuric acid in 40 ml of ethanol) were added thereto. After incubationat 35° C. for 3 hours, the absorption was measured at 573 nm. Thehydroxyproline content, based on the dry weight of the liver samplesemployed, was found from these absorption values by means of acalibration plot.

2.3 Results:

As shown in Table 2, the compounds of the invention reduce the contentof scar collagen in rats with hepatic fibrosis generated by bile ductligature. It is evident from Table 3 that fibrosis generated by carbontetrachloride in the animal model is also inhibited by compounds of theinvention, because the total liver collagen content is reduced onadministration of the substance. Table 4 demonstrates the effect ontotal collagen in serum-induced hepatic fibrosis. TABLE 2 Effect on thecontent of fibrotic tissue in hepatic fibrosis following bile ductligature in rats Animals Intact (Sham- Bile duct Bile duct operated)ligated ligated Administration of Solutol/ethanol/ Solutol/ethanol/ 15mg/kg substance PBS PBS Ex. 82 p.o. b.i.d. in Tolutol/etha- nol/PBSProportionate area 0.21 7.4 4.98 stainable with picrosirius red: averagein % S.E.M. 0.03 0.72 0.58 N (number of animals) 5 11 11 P <0.05 vs.vehicle

This effect corresponds to an inhibition of approx. 34% in fibrosis.TABLE 3 Effect on total collagen in hepatic fibrosis resulting fromchronic administration of carbon tetrachloride in rats Animals IntactCCl₄ CCl₄ Administration Solutol/ethanol/ Solutol/ethanol/ 30 mg/kg Ex.82 of substance PBS PBS p.o. o.d. in Solutol/ethanol/ PBS4-Hydroxyproline 0.504 1.921 1.260 content: average in mg/g dry weightS.E.M. 0.019 0.308 0.121 N (number of 5 11 11 animals) P =0.059 vs.vehicle

TABLE 4 Effect on total collagen in serum-induced hepatic fibrosis inrats Animals Intact Serum-treated Serum-treated AdministrationSolutol/ethanol/ Solutol/ethanol/ 3 mg/kg Ex. of substance PBS PBS 34p.o. o.d. in Solutol/ ethanol/PBS 4-Hydroxyproline 0.577 2.070 1.293content: average in mg/g dry weight S.E.M. 0.038 0.188 0.180 N (numberof 5 15 15 animals) P <0.001 <0.01B. ExamplesAbbreviations:

-   APCI Atmospheric pressure—chemical ionization (in MS)-   Boc tert-Butoxycarbonyl-   DCI Direct chemical ionization (in MS)-   Decomp. Decomposition-   DMAP 4-N,N-Dimethylaminopyridine-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   EDC N′-(3-Dimethylaminopropyl)-N-ethylcarbodiimide×HCl-   EI Electron impact ionization (in MS)-   eq Equivalent(s)-   ESI Elektrospray ionization (in MS)-   HOBt 1-Hydroxy-1H-benzotriazole×H₂O-   HPLC High pressure, high performance liquid chromatography-   LC-MS Coupled liquid chromatography-mass spectroscopy.-   MOM Methoxymethyl-   m.p. Melting point-   NMR Nuclear magnetic resonance spectroscopy-   R_(f) Retention index (in TLC)-   R_(t) Retention time (in HPLC)-   TLC Thin-layer chromatography    Analytical Methods:    Mass Spectroscopic Methods:-   A: DCI, NH₃;-   B: ESI;-   C: ESIpos;-   D: LC-MS/ESIpos;-   E: APCI;-   F: LC-MS    Standard HPLC Method:

Column: Kromasil C-18 125×2 mm; flow rate: 0.5 ml/min; wavelength: 210nm; temp.: 30° C.; eluent: gradient of CH₃CN/0.01 M H₃PO₄

General Preparation Processes:

General Method (1)

Variant (1a):

Amine (1.8-2.0 eq.) and triethylamine (1.5 eq) as auxiliary base areadded to a suspension of 4,5-dihalopyridazin-3-one derivative (1 eq.) in1,2-dichloroethane. (0.4-0.5 mol/l). The mixture is heated to reflux for15-20 h and, after cooling, diluted with dichloromethane. It is washedwith 0.5 N hydrochloric acid solution and saturated sodium chloridesolution, dried over magnesium sulfate and concentrated. The crudeproduct is purified by crystallization from dichloromethane/diethylether mixtures or by chromatography on silica gel(dichloromethane/methanol mixtures).

Variant (1b):

Amine (1-3 eq.) and sodium iodide (8-10 mol %; catalytic amount) areadded to a solution of 4,5-dihalopyrazin-3-one derivative (1 eq.) inN-methyl-2-pyrrolidine (NMP) and stirred at 65° C. for 4-8 h. Aftercooling, water is added, and the precipitate product is filtered offwith suction. The residue on the filter is stirred in diethyl ether,filtered off with suction and dried under high vacuum.

Variant (1c): Dichloromethane or Dioxane Process

The amine (1-7 eq.) is slowly added to a suspension of4,5-dichloropyrazin-3-one derivative (1 eq.) in dichloromethane ordioxane (in the case of dioxane, catalytic amounts of sodium iodide areadded) and heated to reflux for 20 h. Cooling is followed by washingwith 1 molar sodium hydroxide solution, and the dichloromethane phase isdried with sodium sulfate and concentrated. In the case of dioxane, thesolvent is distilled off and the residue is partitioned indichloromethane/water, and the organic phase is separated off andconcentrated. Crystallization is effected by stirring the residue withether.

General Method (2)

(Method for Acylation of Amine/Aniline Fragments in R¹, R² and R³)

Example:

Acylating reagent (anhydride or acid chloride, 1.2-2.0 eq.) is added toa solution of an amine or aniline derivative (1 eq.) in absolute1,2-dichloroethane (0.25-0.5 mol/l) cooled in ice. After conversion iscomplete (a catalytic amount of 4-DMAP is added where appropriate), thereaction mixture is warmed to room temperature and diluted withdichloromethane. It is washed with 1 N hydrochloric acid solution,saturated sodium bicarbonate solution and saturated sodium chloridesolution, dried over magnesium sulfate and concentrated. The crudeproduct is purified by crystallization from dichloromethane/diethylether mixture or by chromatography on silica gel(dichloromethane/methanol mixtures).

General Method (3)

(Method for Formylation of Amine/Aniline Fragments in R¹, R² and R³)

Example:

A mixture of formic acid (2.5 eq.) and acetic anhydride (2.0 eq.) isheated at 50° C. for 1 h and, after cooling, diluted with absolutedichloromethane (0.5 mol/l) and added to a mixture of amine or anilinederivative (1.0 eq.) and pyridine (3.0 eq.) in dichloromethane (0.5mol/l). The reaction mixture is stirred at room temperature for severalhours before being diluted with dichloromethane, washed with water andsaturated sodium bicarbonate solution, dried over magnesium sulfate andconcentrated. The crude product is purified where appropriate bycrystallization from dichloromethane/diethyl ether mixtures.

General Method (4)

(Method for Mesylation of Amine/Aniline Fragments in R¹, R² and R³)

Example:

Methanesulfonyl chloride (1.2-2.0 eq.) is added dropwise to a solutionof an amine or aniline derivative (1 eq.) and an auxiliary base(pyridine or triethylamine, 2.0-3.0 eq.) in absolute dichloromethane(0.25-0.5 mol/) cooled in ice. After conversion is complete, thereaction solution is warmed to room temperature and diluted withdichloromethane. It is washed with 1 N hydrochloric acid solution,saturated sodium bicarbonate solution and saturated sodium chloridesolution, dried over magnesium sulfate and concentrated. The crudeproduct is purified by crystallization from dichloromethane/diethylether mixtures or by chromatography on silica gel(dichloromethane/methanol mixtures).

General Method (5)

(Method for Carbamoylation of Amine/Aniline Fragments in R¹, R² and R³)

Example:

Trimethylsilyl isocyanate (8.0 eq.) is added dropwise to a mixture of anamine or aniline derivative (1 eq.) in absolute dichloromethane. Thereaction mixture is stirred at room temperature over night and thenconcentrated and dried under high vacuum, and the residue is taken up indichloromethane. The solution is washed with water, 2 N potassiumcarbonate solution and saturated sodium chloride solution, dried overmagnesium sulfate and concentrated. The residue is purified bychromatography on silica gel or preparative thin-layer chromatography(dichloromethane/methanol mixtures).General Method (6)

Variant (6-a), Potassium Salt Method:

A phenol derivative (3.0 eq.) is introduced in portions into a solutionof potassium tert-butoxide (3.0 eq.) in absolute tetrahydrofuran (0.5mol/l). After 30 min at room temperature, the solution is concentratedand the residue is dried under high vacuum. 4-Halopyridazin-3-onederivative (1.0 eq.), potassium iodide (0.1 eq.) and absolutedimethylformamide (0.5 ml/l) are added to the dried potassium phenolate.The mixture is stirred vigorously in an oil bath at 170° C. for 20-30min before being cooled and the solvent being removed under high vacuum.The residue is taken up in dichloromethane and washed with 1 N sodiumhydroxide solution (twice) and saturated sodium chloride solution, driedover magnesium sulfate and concentrated. The crude product is purifiedby crystallization from dichloromethane/diethyl ether mixtures or bychromatography on silica gel (dichloromethane/methanol mixtures).

Variant (6-b), Cesium Salt Method:

A phenol derivative (3.0 eq.), is introduced in portions into asuspension of cesium carbonate (1.5 eq.) in absolute methanol (0.5mol/l). After 1 h at room temperature, the clear solution isconcentrated and the residue is dried under high vacuum.4-Halopyridazin-3-one derivative (1.0 eq) and absolute dimethylformamide(approx. 0.3 mol/l) are added to the dried cesium phenolate. The mixtureis stirred vigorously at 120° C. overnight before being cooled and thesolvent being removed under high vacuum. The residue is taken up indichloromethane and washed with water, 1 N sodium hydroxide solution andsaturated sodium chloride solution, dried over magnesium sulfate andconcentrated. The crude product is purified by crystallization fromdichloromethane/diethyl ether mixtures or by chromatography on silicagel (dichloromethane/methanol mixtures).Variant (6-c), via 4-aryloxy-5-halopyridazin-3-one Derivatives:

A mixture of a 4-aryloxy-5-halopyridazin-3-one derivative (1.0 eq., seemethod 12 for preparation) and a cyclic amine derivative (1.2 to 1.5eq.), potassium iodide (1.0 eq.) and ethyldiisopropylamine (2.0 eq.) inabsolute dimethylformamide is heated at 120° C. to 140° C. for 8 to 18h. Cooling is followed by concentration under high vacuum, and theresidue is taken up in dichloromethane. The solution is washed withdilute hydrochloric acid solution and saturated sodium chloridesolution, dried over magnesium sulfate and concentrated in vacuo. Theproduct is obtained from the crude mixture by chromatography on silicagel (dichloromethane/methanol mixtures) or by crystallization fromdiethyl ether or diethyl ether/dichloromethane mixtures.

Variant (6-d), Reaction in the Melt [Variant of Method (6a)]:

The potassium salt of a phenol is stirred with 4-halopyrazin-3-onederivatives (1 eq.) in DMF in an oil bath preheated to 175° C. for 30min. Cooling to room temperature is followed by dilution withdichloromethane and washing with 1 molar sodium hydroxide solution. Theorganic phase is dried with sodium sulfate and concentrated. The crudeproduct is purified by crystallization or by chromatography on silicagel (toluene/acetonitrile mixtures).

General Method (7)

(Method for Liberating Amine/Aniline Fragments in R¹, R² and R³ fromBoc-Protected Precursors)

Example:

An ice-cooled mixture of tert-butyloxycarbonate (Boc)-protected amine(1.0 eq.) in dichloromethane (approx. 0.15 mol/l, addition of 2% water)is mixed with trifluoroacetic acid (60% of the amount ofdichloromethane). The mixture is stirred vigorously at room temperaturefor about 3 h before being concentrated and dried under high vacuum. Theresidue is taken up in dichloromethane, washed with saturated sodiumbicarbonate solution and saturated sodium chloride solution, dried overmagnesium sulfate and concentrated. The crude product is purified bycrystallization from dichloromethane/diethyl ether mixtures or bychromatography on silica gel (dichloromethane/methanol mixtures).

Aryl bromide (1.0 eq., see method 6 for preparation),bis(pinacolato)diboron (1.1 eq.), potassium acetate (3.0 eq.), DMSO andPdCl₂(dppf) (0.04. eq.) are successively put into a flask flushed withargon. The mixture is stirred vigorously at 80° C. under argon. Afterconversion is complete (checked by HPLC), the mixture is cooled, dilutedwith dichloromethane and washed twice with water. It is dried overmagnesium sulfate and concentrated. The crude product is purified bychromatography on silica gel (dichloromethane/methanol mixtures) with,where appropriate, crystallization from dichloromethane/diethyl ethermixtures.

General Method (9)

Example:

Variant (9-a), via Boronic Acid Derivatives:

Aryl bromide (1.0 eq., see method 6 for preparation), arylboronic acidderivative (1.2-2.0 eq.), PdCl₂(dppf) (0.05 eq.), dimethylformamide(approx. 0.15 mol/l) and sodium carbonate (2.5 to 5.0 eq., as 2 Naqueous solution) are successively put into a flask flushed with argon.The mixture is vigorously stirred at 80° C. under argon (usuallyovernight) before being cooled and then concentrated under high vacuum.The residue either undergoes aqueous workup or is filtered through asilica gel column (dichloromethane/methanol mixtures). The crude productis purified by crystallization from dichloromethane/diethyl ethermixtures, by chromatography on silica gel (dichloromethane/methanolmixtures) or by preparative thin-layer chromatography(dichloromethane/methanol mixtures).Variant (9-b), via Borinate Ester Derivatives:

Aryl bromide or iodide (2.0 eq.), arylborinate ester derivative (1.0eq., see method 8 for preparation), PdCl₂(dppf) (0.05 eq.),dimethylformamide (approx. 0.15 mol/l) and sodium carbonate (5.0 eq., as2 N aqueous solution) are successively put into a flask flushed withargon. The mixture is stirred vigorously at 80° C. under argon (usuallyovernight) before being cooled and then concentrated under high vacuum.The residue either undergoes aqueous workup or is filtered through asilica gel column (dichloromethane/methanol mixtures). The crude productis purified by crystallization from dichloromethane/diethyl ethermixtures, by chromatography on silica gel (dichloromethane/methanolmixtures) or by preparative thin-layer chromatography(dichloromethane/methanol mixtures).

Variant (9-c), via Borinate Ester Derivatives Generated in Situ:

Aryl bromide (1.0 eq., see method 6 for preparation),bis(pinacolato)diboron (1.1 eq.), potassium acetate (3.0 eq.), DMSO andPdCl₂(dppf) (0.04 eq.) are put successively into a flask flushed withargon. The mixture is stirred vigorously at 80° C. under argon. Afterconversion is complete (checked by HPLC), the mixture is cooled andfiltered (aliquots can be taken at this point from parallel syntheticbatches). Aryl bromide or iodide (2.0 eq.), PdCl₂(dppf) (0.05 eq.) andsodium carbonate (5.0 eq., as 2 N aqueous solution) are addedsuccessively to the resulting solution under argon. The reaction mixtureis stirred vigorously at 80° C. under argon (usually overnight) beforebeing cooled and then the crude products being obtained either byaqueous workup (addition of water and dichloromethane with subsequentphase separation through Chromaphil filter) or by precipitation afteraddition of water. Further purification takes place by chromatography onsilica gel (dichloromethane/methanol mixtures), preparative thin-layerchromatography (dichloromethane/methanol mixtures) or preparativeRP-HPLC; crystallization from dichloromethane/diethyl ether mixturestakes place where appropriate.

General Method (10)

(Method for Liberation of Phenol Fragments in R² and R³ fromMOM-Protected Precursors)

Example:

A mixture of a methoxymethyl (MOM)-protected phenol derivative in amixture of acetic acid, water and trifluoroacetic acid (3:1:1, approx.0.1 to 0.2 mol/l) is stirred vigorously at room temperature untilconversion is complete. The reaction mixture is concentrated and driedunder high vacuum. The residue is washed with saturated sodiumbicarbonate solution and sodium chloride solution, dried over magnesiumsulfate and concentrated. The product is purified if necessary bycrystallization from dichloromethane/diethyl ether mixtures, bychromatography on silica gel (dichloromethane/methanol mixtures) or bypreparative thin-layer chromatography (dichloromethane/methanolmixtures).

General Method (11)

(Method for Etherification of Phenol Fragments in R² and R³)

Example:

An excess of methyl iodide (approx. 5.0 to 10 eq.), is added dropwise toa mixture of a phenol derivative (1.0 eq.) and potassium carbonate (2.0eq.) in absolute tetrahydrofuran (approx. 0.1 mol/l). The reactionmixture is heated to reflux (usually overnight) and, after cooling,evaporated to dryness and mixed with water. The product obtained afterfiltration and drying under high vacuum is further purified whereappropriate by crystallization from dichloromethane/diethyl ethermixtures or by preparative thin-layer chromatography(dichloromethane/methanol mixtures).General Method (12)

Sodium hydride (1.0 eq., 60% in mineral oil) is introduced in portionsinto a water-cooled solution of a phenol derivative (1.0 eq.) inabsolute 1,4-dioxane (0.4 mol/l) while stirring vigorously (an inverseprocedure is advisable for larger batches). After 1 h the solution isadded at room temperature to a suspension of a 4,5-dihalopyridazin-3-onederivative (1.0 eq.) in absolute 1,4-dioxane (0.4 mol/l). The reactionmixture is stirred vigorously at room temperature for 15-20 h before thedioxane is almost completely removed in vacuo. The residue is taken upin dichloromethane, washed with water and saturated sodium chloridesolution, dried over magnesium sulfate and concentrated. The product isobtained from the mixture by crystallization from dichloromethane or bychromatography on silica gel (dichloromethane/cyclohexane mixtures).General Method (13)

A suspension of a 5-halopyridazin-3-one derivative (1.0 eq., see method12 for preparation) and sodium azide (5.0 eq.) in dimethylformamide (0.5mol/l) is heated at 50-55° C. for 30 to 45 min. Cooling is followed bydilution with dichloromethane, washing with water and saturated sodiumchloride solution, drying over magnesium sulfate and cautiouslyconcentrating. The residue dried under high vacuum is crystallized usingdichloromethane/diethyl ether.

General Method (14)

(Method for 1,2,3-triazole Synthesis)

Example:

A suspension of 5-azidopyridazin-3-one derivative (1.0 eq., see method13 for preparation) and of a mono- or disubstituted alkyne derivative(2.0 to 8.0 eq.) in toluene (0.1 to 0.4 mol/l) is heated to reflux (2 to24 h). After cooling, the reaction mixture is concentrated and theproduct mixture is separated into the regioisomers which have beenproduced where appropriate, and purified, by crystallization fromdiethyl ether or diethyl ether/dichloromethane mixtures andchromatography on silica gel (dichloromethane/methanol mixtures).General Method (15)

Variant (15a), 4-chloro-5-(1H-imidazol-1yl)-2-aryl-3(2H)-pyridazinones:

25 mmol of 4,5-dichloro-2-aryl-2(3H)-pyridazinone, 75 mmol of imidazoleand 0.7 mmol of sodium iodide in 100-150 ml of dimethylformamide arestirred at 90° C. for 8 h (TLC check). Cooling to room temperature isfollowed by dilution with water and extraction several times withdichloromethane. The organic phase is washed with water and dried oversodium sulfate. The crude product remaining after concentration in arotary evaporator is chromatographed on silica gel (0.063-0.2 mm).Excess precursor is initially eluted with dichloromethane; the desiredproduct is obtained by elution with petroleum ether/ethyl acetate 1:1.Evaporation results in the appropriate4-chloro-5-(1H-imidazol-1-yl)-2-aryl-3(2H)-pyridazinones.

Variant (15b), 4-bromo-5-(1H-imidazol-1-yl)-2-aryl-3 (2H)-pyridazinones:

On use of 4,5-dibromo-2-aryl-2(3H)-pyridazinones, the corresponding4-bromo derivatives are obtained in analogy to method (19a).

The appropriate 4,5-dibromo- and 4,5-dichloro-2-aryl-2(3H)-pyridazinonesare known or can be prepared by known processes from commerciallyavailable arylhydrazines and mucobromic or mucochloric acid under acidicconditions [H. R. Hensel and G. Lüitzel, Angewandte Chemie 77, 303(1965].General Method (16)

Variant (16a):

10 mmol of 4-chloro- or4-bromo-5-(1H-imidazol-1-yl)-2-aryl-3(2H)-pyridazinone, 15.0 mmol ofphenol, 0.1 g of sodium iodide and 12 mmol of1,4-diaza-bicyclo[2.2.2]octane are taken up in 4-10 ml ofdimethylformamide and heated at 100° C. overnight. Cooling is followedby dilution with dichloromethane. The organic phase is washed withdilute hydrochloric acid (pH 3), water, 1 N sodium hydroxide solutionand water. The residue remaining after drying over sodium sulfate andconcentrating is stirred with diethyl ether/methanol 95:5. Purificationby chromatography (silica gel 0.063-0.2 mm, dichloromethane/methanol40:1) of the mother liquor results in further target compound.

Variant (16b):

1,4-Diazabicyclo[2.2.2]octane can be replaced by sodium hydride.

Variant (16c):

1,4-Diazabicyclo[2.2.2]octane can be replaced by sodium methoxide. Thesodium salt is formed in analogy to method (6a) beforehand, and thesolvent is concentrated.General Method (17)

1.1 mmol of2-(4-nitrophenyl)-5-(1H-imidazol-1-yl)-4-aryloxy-3(2H)-pyridazinone in50ml of glacial acetic acid are hydrogenated in the presence of 0.05 gof palladium on activated carbon (10%) at room temperature under 3 bar.After 4 hours, the catalyst is filtered off, and the filtrate isconcentrated and taken up in dichloromethane. The organic phase iswashed with 1 N sodium bicarbonate solution and water. After drying andconcentration, the desired 2-(4-aminophenyl)-3(2H)-pyridazinone isobtained by chromatography on silica gel (0.063-0.2 mm, ethyl acetate).

The products obtained from the general preparation processes can betreated with solutions of hydrogen chloride in inert solvents to obtainthe corresponding hydrochlorides.

Starting Compounds and Intermediates:

EXAMPLE 1A tert-Butyl4-[5-chloro-1-(4-chlorophenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-1-piperazinecarboxylate

By general method 1 from 20.66 g (75 mmol) of2-(4-chlorophenyl)-4,5-dichloro-pyridazin-3-one with 25.14 g (135 mmol)of Boc-piperazine.

Yield: 25.22 g (79.1% of theory)

MS (Method A): m/z=442 (M+NH₄)⁺, 425 (M+H)⁺

HPLC: R_(t)=9.51 min.

EXAMPLE 2A4-Chloro-2-(4-chlorophenyl)-5-(1-piperazinyl)-3(2H)-pyridazinone

55.1 g (200 mmol) of 2-(4-chlorophenyl)-4,5-dichlorpyridazin-3-one areintroduced with 41.6 ml (300 mmol) of triethylamine in 400 ml ofdimethylformamide. 137.82 g (1600 mmol) of piperazine are added, and themixture is stirred at 80° C. overnight. The reaction mixture is cooledand then concentrated under high vacuum. The residue is taken up indichloromethane and washed twice with water, dried over magnesiumsulfate and concentrated. The product is isolated by chromatography(gradient: dichloromethane/methanol from 95:5 to 9:1) on silica gel andsubsequent crystallization with ether.

Yield: 40.9 g (62.9% of theory)

MS (Method A): m/z=325 (M+H)⁺

HPLC: R_(t)=5.38 min.

EXAMPLE 3A5-(4-Acetyl-1-piperazinyl)-4-chloro-2-(4-chlorophenyl)-3(2H-pyridazinone

Obtainable by general method 2 from 9.76 g (30 mmol) of the compoundfrom Example 2A with 5.7 ml (60 mmol) of acetic anhydride.

Yield: 10.6 g (96.2% of theory)

MS (Method B): m/z=367 (M+H)⁺

HPLC: R_(t)=7.01 min.

EXAMPLE 4A5-(4-Acetyl-1-piperazinyl)-4-chloro-2-(4-methylphenyl)-3(2H)-pyridazinone

Obtainable by general method 1 from 10.0 g (39.2 mmol) of2-(4-chlorophenyl)-4,5-dichloropyridazin-3-one with 8.2 g (64 mmol) ofN-acetylpiperazine.

Yield: 7.86 g (57.8% of theory)

MS (Method F): m/z=347 (M+H)⁺

HPLC: R_(t)=6.67 min.

EXAMPLE 5A4-Chloro-2-(4-chlorophenyl)-5-[4-(cyclopropylcarbonyl)-1-piperazinyl]-3(2H)-pyridazinone

Obtainable by general method 2 from 9.76 g (30.0 mmol) of the compoundfrom Example 2A with 3.3 ml (36 mmol) of cyclopropylcarbonyl chloride.

Yield: 11.22 g (95.1% of theory)

MS (Method F): m/z=393 (M⁺)

HPLC: R_(t)=7.72 min.

EXAMPLE 6A4-Chloro-2-(4-chlorophenyl)-5-[4-(methylsulfonyl)-1-piperazinyl]-3(2H)-pyridazinone

Obtainable by general method 4 from 10.0 g (30.75 mmol) of the compoundfrom Example 2A with 3.6 ml (46.1 mmol) of methanesulfonyl chloride.

Yield: 11.1 g (89.5% of theory)

MS (APCI): m/z=403 (M+H)⁺

HPLC: R_(t)=7.81 min.

EXAMPLE 7A4-Chloro-2-(4-chlorophenyl)-5-(3-oxo-1piperazinyl)-3(2H)-pyridazinone

Obtainable by general method 1 from 4.68 g (17 mmol) of2-(4-chlorophenyl)-4,5-di-chloropyridazin-3-one with 3.06 g (30.6 mmol).

Yield: 3.51 g (60.9% of theory)

MS (EI-POS): m/z=338 (M⁺)

HPLC: R_(t)=6.42 min.

EXAMPLE 8A4,5-Bis(1,1′-biphenyl-4-yloxy)-2-(4-chlorophenyl)-3(2H)-pyridazinone

68.09 g (400 mmol) of biphen-4-ol are added in portions to a solution of44.9 g (400 mmol) of potassium tert-butoxide in 680 ml of absolutetetrahydrofuran. After 15 min, the solution is concentrated andthoroughly dried under high vacuum. 27.3 g (100 mmol) of2-(4-chlorophenyl)-4,5-dichlorpyridazin-3-one, 8.30 g (50 mmol) ofpotassium iodide and 300 ml of absolute dimethylformamide are added, andthe mixture is heated at 140° C. while stirring vigorously for 4 h.Cooling is followed by concentration under high vacuum, and the residueis taken up in dichloromethane. The suspension is filtered throughCelite and the filtrate is washed twice with 1 N sodium hydroxidesolution. The organic phase is dried over magnesium sulfate andconcentrated. The product is isolated by filtration through a silica gelcolumn (dichloromethane/cyclohexane 3:1).

Yield: 10.20 g (18.8% of theory)

MS (Method B): m/z=543 (M+H)⁺

HPLC: R_(t)=11.85 min.

EXAMPLE 9A4-(1,1′-Biphenyl-4-yloxy)-5-chloro-2-(4-chlorophenyl)-3(2H)-pyridazinone

Obtainable by general method 12 from 22.04 g (80.0 mmol) of2-(4-chlorophenyl)-4,5-dichloropyridazin-3-one.

Yield: 19.54 g (59.7% of theory)

MS (Method B): m/z=409 (M+H)⁺

HPLC: R_(t)=10.95 min.

EXAMPLE 10A 4-(4-Bromophenoxy)-5-chloro-2-(4-chlorophenyl)-3(2H)-pyridazinone

Obtainable by general method 12 from 27.55 g (100.0 mmol) of2-(4-chlorophenyl)-4,5-dichloropyridazin-3-one.

MS (Method B): m/z=428/430 (M+NH₄)⁺

HPLC: R_(t)=10.48 min.

EXAMPLE 11A5-Bromo-2-(4-chlorophenyl)-4-[(4′-fluoro-1,1′-biphenyl-4-yl)oxy]-3(2H)-pyridazinone

Obtainable by general method 12 from2-(4-chlorophenyl)-4,5-dibromopyridazin-3-one.

HPLC: R_(t)=10.96 min.

EXAMPLE 12A5-Chloro-2-(4-chlorophenyl)-4-{[4′-fluoro-2′-(methoxymethoxy)-1,1′-biphenyl-4-yl]-oxy}-3(2H)-pyridazinone

Obtainable by general method 12 from 1.82 g (6.6 mmol) of2-(4-chlorophenyl)-4,5-dichloropyridazin-3-one.

Yield: 1.84 g (57.3% of theory)

MS (Method A): m/z=487/489 (M+H)⁺

HPLC: R_(t)=10.91 min.

EXAMPLE 13A5-Chloro-2-(4-chlorophenyl)-4-[(2′,4′-difluoro-1,1′-biphenyl-4-yl)oxy]-3(2H)-pyridazinone

Obtainable by general method 12 from 5.51 g (20.0 mmol) of2-(4-chlorophenyl)-4,5-dichloropyridazin-3-one.

Yield: 5.07 g (56.9% of theory)

MS (Method A): m/z=462 (M+N)⁺

HPLC: R_(t)=10.97 min.

EXAMPLE 14A5-Azido-4-(1,1′-biphenyl-4-yloxy)-2-(4-chlorophenyl)-3(2H)-pyridazinone

Obtainable by general method 13 from 2.05 g (5.0 mmol) of the compoundfrom Example 9A with 1.63 g (25.0 mmol) of sodium azide.

Yield: 0.998 g (48.0% of theory)

MS (Method B): m/z=416 (M+H)⁺

HPLC: R_(t)=10.74 min.

EXAMPLE 15A5-Azido-4-(4-bromophenoxy)-2-(4-chlorophenyl)-3(2H)-pyridazinone

Obtainable by general method 13 from 7.55 g (18.3 mmol) of the compoundfrom Example 10A with 5.96 g (91.6 mmol) of sodium azide.

Yield: 3.73 g (48.6% of theory)

MS (Method A): m/z=435/437 (M+H)⁺

HPLC: R_(t)=10.25 min.

EXAMPLE 16A5-Azido-2-(4-chlorophenyl)-4-[(4′-fluoro-1,1′-biphenyl-4-yl)oxy]-3(2H)-pyridazinone

Obtainable by general method 13 from 800 mg (1.70 mmol) of the compoundfrom Example 11A.

Yield: 455 mg (55.7% of theory)

MS (Method A): m/z=451 (M+NH₄)⁺, 434 (M+H)⁺

HPLC: R_(t)=10.70 min.

EXAMPLE 17A5-Azido-2-(4-chlorophenyl)-4-{[4′-fluoro-2′-(methoxymethoxy)-1,1′-biphenyl-4-yl]-oxy}-3(2H)-pyridazinone

Obtainable by general method 13 from 305 mg (0.626 mmol) of the compoundfrom Example 12A.

Yield: 118 mg (38.2% of theory)

MS (Method D): m/z=494 (M+H)⁺

HPLC: R_(t)=10.74 min.

EXAMPLE 18A5-Azido-2-(4-chlorophenyl)-4-[(2′,4′-difluoro-1,1′-biphenyl-4-yl)oxy]-3(2H)-pyridazinone

Obtainable by general method 13 from 890.5 mg (2.0 mmol) of the compoundfrom Example 13A.

Yield: 379 mg (37.7% of theory)

MS (Method D): m/z=452 (M+H)⁺

HPLC: R_(t)=10.77 min.

EXAMPLE 19A 4-(tert-Butoxycarbonyl)-R-(−)-2-methylpiperazine

8.49 g (37.74 mmol) of di-tert-butyl pyrocarbonate and catalytic amountsof 4-dimethylaminopyridine are added to a solution of 3.6 g (35.94 mmol)of R-(−)-2-methylpiperazine in 50 ml of tetrahydrofuran, and the mixtureis stirred at room temperature for 24 h. It is evaporated to dryness,taken up in dichloromethane and washed three times with water and oncewith sodium chloride solution, and the organic phase is concentrated.

Yield: 4.62 g (64.2% of theory)

MS (Method A): m/z=318 (M₂+H)⁺

DC: R_(f)=0.29 (dichoromethane/methanol 9:1)

EXAMPLE 20A 4-(tert-Butoxycarbonylamino)-1-carboethoxypiperidine

26.13 g (119.72 mmol) of di-tert-butyl pyrocarbonate and catalyticamounts of 4-dimethylaminopyridine are added to a solution of 10.2 g(58.06 mmol) of 4-amino-1-carbethoxypiperidine in 250 ml oftetrahydrofuran at 0° C. The mixture is allowed to reach roomtemperature and then stirred for 2 h. The reaction solution isconcentrated, and the residue is dissolved in dichloromethane and washedwith water and sodium chloride solution. The organic phase isconcentrated and dried under high vacuum.

Yield: 20.2 g (127.7% d of theory, product contains solvent)

MS (Method A): m/z=290 (M+NH₄)⁺, 273 (M+H)⁺

EXAMPLE 21A 4-(tert-Butoxycarbonylamino)piperidine

19.91 g (0.073 mol) of the compound from Example 20A are added to amixture of 32.33 g (0.576 mol) of KOH in 175 ml of water and 175 ml ofethanol and heated to reflux for 4 h. The reaction solution is thenstirred at room temperature overnight, diluted with 350 ml of conc.sodium chloride solution and extracted four times with a total of 1500ml of ethyl acetate. The organic extract is washed four times with 100ml of sodium chloride solution each time, dried over sodium acetate,concentrated and dried under-high vacuum.

Yield: 11.49 g (89.2% of theory)

MS (Method A): m/z=201 (M+H)⁺

EXAMPLE 22A2-Chloro-2-(4-chlorophenyl)-5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2H-pyridazin-3-one

25.98 g (0.181 mol) of piperidinone 4-ethylene ketal 1.023 g (6.82 mmol)of sodium iodide are successively added to a solution of 20.0 g (72.59mmol) of 4,5-dichloro-2-(4-chlorophenyl)-2-(3H)-pyridazinone in 200 mlof N-methyl-2-pyrrolidine and stirred at 65° C. for 4 h and at roomtemperature overnight. The reaction mixture is stirred into a largeamount of water, and the precipitated product is filtered off withsuction. The residue on the filter is stirred in ether, filtered offwith suction and dried in vacuo.

Yield: 25.36 g (91.4% of theory)

MS (Method B): m/z=382 (M+H)⁺

HPLC: R_(t)=8.49 min.

EXAMPLE 23A tert-Butyl4-[5-chloro-1-(4-chlorophenyl)-6-oxo-1,6-dihydropyridazin-4-yl]-3-methylpiperazine-1-carboxylate

By general method 1c, 15.47 g (80.6 mmol) of tert-butylpiperazine-1-carboxylate and 0.22 g (1.49 mmol) of sodium iodide areadded to a suspension of 10.09 g (30.3 mmol) of2-(4-chlorophenyl)-4,5-dichloro-2(3H)-pyridazinone in 1000 ml of dioxaneand stirred at 100° C. overnight. Dioxane is distilled off, and theresidue is dissolved in dissolved in 200 ml of dichloromethane and 150ml of water. The organic phase is dried, concentrated and stirred with200 ml of ether for 1 h. The crystals are filtered off with suction,washed with ether and dried in vacuo.

Yield: 9.6 g (62.2% of theory)

MS (EI): m/z=424(M⁺)

HPLC: R_(t)=9.54 min.

EXAMPLE 24A4-(4-Bromophenoxy)-2-(4-chlorophenyl)-5-[4-(2-hydroxyethyl)-1-piperazinyl]-3(2H)-pyridazinone

1.35 ml (18.11 mmol) of 2-bromoethanol are added dropwise to a mixtureof 4.18 (9.05 mmol) of4-(4-bromophenoxy)-2-(4-chlorophenyl)-5-(1-piperazinyl)-3(2H)-pyridazinone(Example 57A), 0.15 g of potassium iodide 3.75 g (27.2 mmol) ofpotassium carbonate in 25 ml of 1,4-dioxane. Stirring under refluxovernight is followed by dilution with dichloromethane and washing twicewith water, drying and concentration. Purification is by flashchromatography on silica gel (gradient: dichloromethane/methanol from99:1 to 97:3).

Yield: 3.5 g (76.4% of theory)

MS (Method A): m/z=505/507 (M+H)⁺

HPLC: R_(t)=6.87 min.

The following intermediates are obtained by general method 8:

EXAMPLE 25A2-(4-Chlorophenyl)-5-(1H-imidazol-1-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenoxy]-3(2H)-pyridazinone

MS (Method C): m/z=490 (M⁺)

HPLC: R_(t)=6.31 min.

EXAMPLE 26A2-(4-Chlorophenyl)-5-[4-(2-hydroxyethyl)-1-piperazinyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3(2H)-pyridazinone

MS (Method B): m/z=553 (M+H)⁺

HPLC: R_(t)=7.42 min.

The intermediates Example 27A-Example 37A listed in Table 5 wereprepared by general process 15a: Example No. Structure Physical dataPrecursor 27A

m.p.: 101° C. 4,5-Dichloro-2-(3- trifluoromethylphenyl)-(3H)-pyridazinone 28A

m.p.: 162° C. 4,5-Dichloro-2-phenyl-(3H)- pyridazinone 29A

m.p.: 157° C. 4,5-Dichloro-2-(4- methylphenyl)-(3H)- pyridazinone 30A

m.p.: 175° C. 4,5-Dichloro-2-(4- chlorophenyl)-(3H)- pyridazinone 31A

m.p.: 176° C. 4,5-Dichloro-2-(3- chlorophenyl)-(3H)- pyridazinone 32A

m.p.: 149° C. 4,5-Dichloro-2-(4- ethoxycarbonylphenyl)-(3H)-pyridazinone 33A

 m.p.: 170-3° C. 2-[4-(tert-Butyl)phenyl]-4,5-dichloro-3(2H)-pyridazinone 34A

  m.p.: 139-41° C. 4,5-Dichloro-2-(2- chlorophenyl)-(3H)- pyridazinone35A

m.p.: 122° C. 4,5-Dichloro-2-(3- fluorophenyl)-(3H)- pyridazinone 36A

m.p.: 181° C. 4,5-Dichloro-2-(4- fluorophenyl)-(3H)- pyridazinone 37A

4,5-Dichloro-2-(4- nitrophenyl)-(3H)- pyridazinone

The intermediates Example 38A-Example 63A listed in Table 6 wereobtained general process 6a: Example Physical data (data in ° C. GeneralNo. Structure relate to the melting point) process Starting material 38A

182° C. 16a Example No. 30A; 4-Bromophenol 39A

MS (A): 423 (M + H) (100) 16a Example No. 29A; 4-Bromophenol 40A

155-7° C. 16a Example No. 32A; 4-Bromophenol 41A

168-70° C. 16a Example No. 27A; 4-Bromophenol 42A

225° C. 16a Example No. 33A; 4-Bromophenol 43A

185-190° C. 16a Example No. 36A; 4-Bromophenol 44A

180-185° C. 16a Example No. 35A; 4-Bromophenol 45A

MS (A): 561/563 (M + H) (100); HPLC: 10.64 (94) 6-a Example No. 23A;4-Bromophenol 46A

MS (B): 462/463 (M + H) (100); HPLC: 6.72 (98) 7 Example No. 45A 47A

MS (B): 475/477 (M + H) (100); HPLC: 7.98 (100) 6-a Example No. 7A;4-Bromophenol 48A

MS (B): 503/505 (M + H); HPLC: 8.48 (91) 6-b Example No. 3A;4-Bromophenol 49A

MS (B): 474/476 (M + H) (100); HPLC: 8.78 (100) 14 Example No. 15A;Propargyl alcohol 50A

MS (B): 539/541 (M + H) (100); HPLC: 9.16 (98) 6-b Example No. 6A;4-Bromophenol 51A

MS (D): 529/531 (M + H) (100); HPLC: 9.12 (93) 6-b Example No. 5A;4-Bromophenol 52A

MS (A): 483/485 (M + H) (100); HPLC: 8.16 (94) 6-b Example No. 4A;4-Bromophenol 53A

MS (A): 423 (M + H) (100) 16a Example No. 29A; 3-Bromophenol 54A

83-86° C. 16a Example No. 30A; 3-Bromophenol 55A

MS (A): 566 (M + NH₄) (100); HPLC: 8.98 (100) 12 2-(4-Chlorophenyl)-4,5-dichloro- pyridazinone; 4-bromophenol 56A

MS (D): 382 (M + H) (87); HPLC: 9.16 (92) 16a Example No. 22A;4-Bromophenol 57A

MS (A): 478 (M + H) (100); HPLC: 8.65 (93) 1; 16a 2-(4-Chlorophenyl)-4,5-dichloro- pyridazinone; 4-hydroxy- piperidine; 4-bromophenol 58A

MS (A): 428 (M + NH₄) (100); HPLC: 10.48 (99) 12 2-(4-Chlorophenyl)-4,5-dichloro- pyridazinone; 4-bromophenol 59A

MS (A): 435 (M + NH₄) (100); HPLC: 10.25 (95) 13 Example No. 10A 60A

MS (C): 506 (M + H) (100); HPLC: 7.93 (92) 5 Example No. 46A 61A

MS (C): 590 (M + H) (100); HPLC: 12.25 (95) 14 Example No. 59A;1-(tert-Butyl- dimethylsilyloxy)- prop-2-yne 62A

crude reacted further 16a Example No. 35A; 4-Bromophenol 63A

crude reacted further 16a Example No. 37A; 4-Bromophenol

EXEMPLARY EMBODIMENTS Example 1N-(4′-{[2-(4-Chlorophenyl)-5-(1H-imidazol-1-yl)-3-oxo-2,3-dihydro-4-pyridazinyl]-oxy}-1,1′-biphenyl-2-yl)-N-(methylsulfonyl)methanesulfonamide

0.06 ml (0.072 mmol) of methanesulfonyl chloride are added dropwise to amixture of 16.5 mg (0.036 mmol) of4-[(2′-amino-1,1′-biphenyl-4-yl)oxy]-2-(4-chlorophenyl)-5-(1H-imidazol-1-yl)-3(2H)-pyridazinone(Example 156), 0.02 ml of triethylamine and a catalytic amount of 4-DMAPin 0.2 ml of absolute dichloromethane at room temperature. After 30 min,the reaction is stopped by adding a little water, and the reactionmixture is filtered directly on a silica gel column (mobile phase:dichloromethane/methanol gradient from 99:1 to 98:2).

Yield: 15.3 mg (69.1% of theory)

MS (ESI): m/z=612 (M+H)⁺

HPLC: R_(t)=8.17 min.

Example 2 tert-Butyl4-[5-({4′-[(2,2-dimethylpropanoyl)oxy]-1,1′-biphenyl-4-yl}oxy)-1-(4-methylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-1-piperazinecarboxylate

0.66 ml of pivaloyl chloride are added dropwise to a suspension of 728mg (1.18 mmol) of tert-butyl4-[5-[(4′-hydroxy-1,1′-biphenyl-4-yl)oxy]-1-(4-methyl-phenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-1-piperazinecarboxylate(Example 46) and a catalytic amount of 4-DMAP in a mixture ofdichloromethane (4.0 ml) and pyridine (0.4 ml) at room temperature. Theheterogeneous reaction mixture is stirred at about 40° C. overnight. Theslightly cloudy suspension is diluted with dichloromethane and washedwith 0.2 N hydrochloric acid solution and saturated sodium chloridesolution, dried over magnesium sulfate and concentrated. The crudeproduct is purified by chromatography on silica gel.

Yield: 568 mg (75.3% of theory)

MS (ESI): m/z=639 (M+H)⁺

HPLC: R_(t)=10.21 min.

Example 34′-{[2-(4-Methylphenyl)-3-oxo-5-(1-piperazinyl)-2,3-dihydro-4-pyridazinyl]oxy}-1,1′-biphenyl-4-ylPivalate Trifluoroacetic Acid Salt

0.2 ml of water and 2.2 ml of trifluoroacetic acid are added dropwise toa solution of 568 mg (0.889 mmol) of the compound from Example 2 in 4.5ml of dichloromethane at room temperature. After 45 min, the reactionmixture is concentrated and thoroughly dried under high vacuum.

Yield: 702 mg (96.5% of theory)

MS (ESI): m/z=539 (M+H)⁺ (free base).

Example 44′-{[5-(4-Ethyl-1-piperazinyl)-2-(4-methylphenyl)-3-oxo-2,3-dihydro-4-pyridazinyl]-oxy}-1,1′-biphenyl-4-ylPivalate

360 mg (0.44 mmol) of the compound from Example 3 are introduced into2.0 ml of acetone, and 0.046 ml (0.57 mmol) of-ethyl iodide and 0.18 ml(1.32 mmol) of triethylamine are successively added. The mixture isstirred at room temperature overnight before being diluted withdichloromethane, washed with saturated sodium bicarbonate solution,dried over magnesium sulfate and concentrated. The crude product ispurified by filtration through a silica gel column (mobile phase:dichloromethane/methanol 95:5).

Yield: 211 mg (84.4% of theory)

MS (ESI): m/z=567 (M+H)⁺

HPLC: R_(t)=7.00 min.

Example 55-(4-Ethyl-1-piperazinyl)-4-[(4′-hydroxy-1,1′-biphenyl-4-yl)oxy]-2-(4-methylphenyl)-3(2H)-pyridazinone

210 mg (0.37 mmol) of the compound from Example 4 are introduced into4.5 ml of dry methanol. Addition of 0.9 ml of triethylamine is followedby heating to reflux for 24 h. The suspension is concentrated and theresulting colorless solid is dried under high vacuum.

Yield: 134 mg (74.9% of theory)

MS (DCI/NH₃): m/z=483 (M+H)⁺

HPLC: R_(t)=6.59 min.

Example 64-[(4′-Hydroxy-1,1′-biphenyl-4-yl)oxy]-2-(4-methylphenyl)-5-(4-methyl-1-piperazinyl)-3(2H)-pyridazinone

360 mg (0.44 mmol) of the compound from Example 3 are introduced into2.0 ml of acetone, and an excess of methyl iodide and 0.18 ml oftriethylamine are successively added. After the reaction has subsided,the mixture is stirred at room temperature for 1 h before being dilutedwith dichloromethane. The precipitated solid is filtered off and thefiltrate is washed with water, dried over magnesium sulfate andconcentrated. The crude product is purified by chromatography on silicagel (mobile phase: dichloromethane/methanol 95:5). The product (23 mg)is dissolved in absolute methanol and, after addition of 0.3 ml oftriethylamine, stirred under reflux for 36 h. Cooling is followed byconcentration, and the resulting product is thoroughly dried under highvacuum.

Yield: 19 mg (9.1% of theory)

MS (DCI/NH₃): m/z=486 (M+NH₄)⁺, 469 (M+H)⁺

HPLC: R_(t)=6.51 min.

Example 75-(4-Ethyl-1-piperazinyl)-4-[(4′-hydroxy-1,1′-biphenyl-4-yl)oxy]-2-(4-methylphenyl)-3(2H)-pyridazinoneHydrochloride

Hydrochloric acid (0.1 ml of a 1 molar solution in 1,4-dioxane) is addedto a mixture of 48.3 mg (0.1 mmol) of the compound from Example 5 in 4.0ml of 1,4-dioxane. After 30 minutes, the white suspension isconcentrated and thoroughly dried under high vacuum.

Yield: 51 mg (98.3% of theory)

MS (DCI/NH₃): m/z=500 (M+NH₄)⁺, 483 (M+H)⁺

HPLC: R_(t)=6.44 min.

Example 84-{[3′-(Aminomethyl)-4′-fluoro-1,1′-biphenyl-4-yl]oxy}-2-(4-chlorophenyl)-5-[4-(methylsulfonyl)-1-piperazinyl]-3(2H)-pyridazinone

The compound from Example 50A is reacted with2-fluoro-5-bromo-(N-tert-butyloxycarbonyl)benzylamine by general method9-c. The coupled product is derivatized by general method 4 to give thecorresponding sulfonamide. The target product is obtained afterelimination of the Boc protective group (general method 7).

MS (ESIpos): m/z=584 (M+H)⁺

HPLC: R_(t)=6.88 min.

Example 92-(4-Chlorophenyl)-4-{[4′-fluoro-3′-(hydroxymethyl)-1,1′-biphenyl-4-yl]oxy}-5-[4-(methylsulfonyl)-1-piperazinyl]-3(2H)-pyridazinone

The compound from Example 50A is reacted with2-fluoro-5-bromo-(O-tert-butyldimethylsilyl)benzyl alcohol by generalmethod 9-c. The coupled product is derivatized by general method 4 togive the corresponding sulfonamide. The resulting intermediate istreated in acetonitrile at 0° C. with HF solution (5% of a 48% strengthsolution) and vigorously stirred at room temperature for 2 h. Thereaction mixture is neutralized with saturated sodium bicarbonatesolution and extracted with dichloromethane. The organic phase is driedover magnesium sulfate and concentrated. The product is thoroughly driedunder high vacuum.

LC-MS (ESIpos): m/z=585/587 (M+H)⁺

HPLC: R_(t)=8.63 min.

Example 102-(4-Chlorophenyl)-5-(1H-imidazol-1-yl)-4-[4-(4-pyridinyl)phenoxy]-3(2H)-pyridazinone

1.5 mmol of4-(4-bromophenyl)oxy-2-(4-chlorophenyl)-5-(1H-imidazol-1-yl)-3(2H)-pyridazinone,2.1 mmol of 4-trimethylstannylpyridine, 0.1 mmol ofbis(triphenyl-phosphine)palladium dichloride and 1.3 mmol ofethyldiisopropylamine in 5 ml of dimethylformamide are heated at 100° C.for 5 hours. The solvent is removed in a rotary evaporator, and theresidue is purified by chromatography on silica gel (elution with ethyl,acetate/methanol mixtures). 0.3 g (45% of theory) is obtained of m.p.188° C.

Example 11 tert-Butyl4-[5-(1,1′-biphenyl-4-yloxy)-1-(4-chlorophenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-1-piperazineCarboxylate

Obtainable by general method 6-d from 9.60 g (22.6 mmol) of the compoundfrom Example 23A and 14.1 g (67.68 mmol) of potassium 4-phenylphenolate.

Yield: 7.37 g (37.6% of theory)

MS (DCI/NH₃): m/z=559 (M+H)⁺

HPLC: R_(t)=11.11 min.

Example 124-(1,1′-Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5-(1-piperazinyl)-3(2H)-pyridazinone

Obtainable by general method 7 from 4.23 g (7.56 mmol) of the compoundfrom Example 11.

Yield: 3.44 g (99.2% of theory)

MS (DCI/NH₃): m/z=459 (M+H)⁺

HPLC: R_(t)=7.19 min.

Example 134-(Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2H-pyridazin-3-one

Obtainable method by 6-d from 6.0 g (15.7 mmol) of the compound fromExample 22A.

Yield: 1.42 g (17.5% of theory)

MS (ESI): m/z=516 (M+H)⁺

HPLC: R_(t)=10.45 min.

Example 144-(Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5-(4-oxo-piperidin-1-yl)-2H-pyridazin-3-one

1.4 g (2.71 mmol) of the compound from Example 13 are stirred in 170 mlof acetone and 85 ml of 6 N hydrochloric acid under reflux for 2 h.After cooling, the solvent is distilled off, ethyl acetate is added, thesolution is washed with saturated sodium carbonate solution and water.The organic phase is dried and concentrated. The residue is stirred withether and filtered off with suction.

Yield: 705 mg (55.1% of theory)

MS (EI): m/z=472 (M+H)⁺

HPLC: R_(t)=9.69 min.

Example 154-(Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5-(4-hydroxypiperidin-1-yl)-2H-pyridazin-3-one

0.2 g (0.424 mmol) of the compound from Example 14 are dissolved in 7 mlof methanol and, at room temperature, 50 mg (1.3 mmol) of sodiumborohydride are added in portions. Stirring for 2 h is followed bydilution with dichloromethane, washing with saturated ammonium chloridesolution, drying over sodium sulfate and concentration. The crudeproduct is stirred with 25 ml of boiling methanol and then cooled andfiltered off with suction.

Yield: 78 mg (39% of theory)

MS (ESI): m/z=474 (M+H)⁺

HPLC: R_(t)=9.27 min.

A 2nd fractions is obtained by concentrating the mother liquor andstirring with dichloromethane:

Yield: 56 mg (27.9% of theory)

Example 164-(Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5-(4-fluoropiperidin-1-yl)-2H-pyridazin-3-one

0.122 g (0.757 mmol) of diethylaminosulfur trifluoride are added to asolution of 15 mg (0.03 mmol) of the compound from Example 15 in 3 ml ofdichloromethane under argon and were cooled in ice. After 4 h, thereaction solution is poured into ammonium chloride solution andextracted three times with dichloromethane. The organic phase is dried,concentrated and purified by chromatography on silica gel (mobile phasegradient from toluene to toluene/acetonitrile 18:1).

Yield: 5.6 mg (37.2% of theory)

MS (ESI): m/z=476 (M+H)⁺

DC: R_(f)=0.37 (toluene/acetonitrile 9:1)

Example 174-(Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5-(4,4-difluoropiperidin-1-yl)-2H-pyridazin-3-one

170 mg (1.06 mmol) of diethylamine-sulfur trifluoride are added dropwiseto a solution of 60 mg (0.127 mmol) of the compound from Example 14 in 5ml of dichloromethane at 0° C. under argon, and the mixture is stirredat 0° C. for 30 min. Stirring is then continued without cooling bath for1.5 h, and the mixture is diluted with dichloromethane and ammoniumchloride solution is added. The organic phase is separated off, driedover sodium sulfate and concentrated. The product is obtained bychromatography on silica gel (mobile phase: 180 ml of toluene/5 ml ofacetonitrile to 180 ml of toluene/15 ml of acetonitrile).

Yield: 31 mg (49.4% of theory)

MS (DCI/NH₃): m/z=494 (M+H)⁺

DC: R_(f)=0.49 (toluene/acetonitrile 8:2)

Example 182-(4-Chlorophenyl)-4-(4′-fluorobiphenyl-4-yloxy)-5-(4-chloropiperidin-1-yl)-2H-pyridazin-3-one

A suspension of 150 mg (0.305 mmol) of2-(4-chlorophenyl)-4-(4′-fluorobiphenyl-4-yloxy)-5-(4-hydroxypiperidin-1-yl)-2H-pyridazin-3-one(obtainable in analogy to Example 15) is heated under reflux with 4 mlof thionyl chloride for 60 min. After cooling, the reaction solution isconcentrated under high vacuum, the residue is partitioned between 50 mlof ethyl acetate and 20 ml of saturated sodium bicarbonate solution, theorganic phase is separated off, and the aqueous phase is extracted threetimes with ethyl acetate. The combined organic phases are dried oversodium sulfate, and the solvent is removed in vacuo. The product ispurified by chromatography on silica gel with toluene/ethyl acetate from9:1 to 8:2 as mobile phase.

Yield: 30.9 mg (18.2% of theory)

MS (ESI): m/z=512 (M+H)⁺

HPLC: R_(t)=11.02 min.

Example 19 Tert-butyl(2-{4-[5-(biphenyl-4-yloxy)-1-(4-chlorophenyl)-6-oxo-1,6-dihydropyridazin-4-yl]piperazin-1-yl}-1-methyl-2-oxo-ethyl)carboxylate

160 mg (0.348 mmol) of the compound from Example 12, dissolved in 1 mlof dichloromethane, are added dropwise to a solution of 92 mg (0.487mmol) of Boc-L-alanine, 93.4 mg (0.487 mmol) of EDC, 65.8 mg (0.487mmol) of HOBt and 0.1 ml (0.717 mmol) of triethylamine in 2 ml oftetrahydrofuran and 10 ml of dichloromethane while stirring under argonat 0° C. The mixture is stirred at room temperature overnight. Thereaction solution is diluted with 100 ml of dichloromethane, washed withsaturated sodium bicarbonate solution and brine, dried over sodiumsulfate and concentrated. The residue is stirred with ether and filteredoff with suction.

Yield: 195.5 mg (89.0% of theory)

MS (ESI): m/z=630 (M+H)⁺

HPLC: R_(t)=10.15 min.

Example 204-(Biphenyl-4-yloxy)-2-(chlorophenyl)-5-(4-L-alanylpiperazin-1-yl)-2H-pyridazin-3-one

Obtainable from 180 mg (0.286 mmol) of the compound from Example 19 bygeneral method 7.

Yield: 80 mg (52.9% of theory)

MS (ESD: m/z=530 (M+H)⁺

HPLC: R_(t)=7.33 min.

Example 214-[5-(4′-Fluorobiphenyl-4-yloxy)-6-oxo-1-(4-trifluoromethylphenyl)-1,6-dihydro-pyridazin-4-yl]piperazine-1-carbaldehyde

First, 613.1 mg (3.13 mmol) of EDC are added to a solution of 288.5 mg(6.27 mmol) of formic acid in 4 ml of dichloromethane, and the mixtureis stirred at 0° C. for 20 minutes. Subsequently, 80 mg (0.157 mmol) of4-(4′-fluorobiphenyl-4-oxy)-2-(4-trifluoromethylphenyl)-5-(piperazin-1-yl)-3(2H)-pyridazinone(obtainable in analogy to Example 12) and 0.1 ml (0.717 mmol) oftriethylamine are added to this reaction solution at 0° C., and themixture is stirred at 0° C. overnight. Aqueous work-up with dilutehydrochloric acid and then saturated sodium bicarbonate solution resultsin a crude product, which is chromatographed on silica gel withdichloromethane/methanol 10:1 as mobile phase.

Yield: 24.6 mg (7.3% of theory)

MS (ESI): m/z=539 (M+H)⁺

HPLC: R_(t)=9.40 min.

Example 224-(Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5(4-cyclopropylpiperazin-1-yl)-2H-pyridazin-3-one

1.77 ml (22.1 mmol) of cyclopropyl bromide are added dropwise to asolution of 150 mg (0.327 mmol) of the compound from Example 40 in 5 mlof DMF and 0.34 ml (2.45 mmol) of triethylamine, and the mixture is thenstirred at 120° C. overnight. The reaction mixture is poured into 150 mlof water and extracted twice with ethyl acetate. The organic phase isdried over sodium sulfate and concentrated. The product is purified bychromatography on silica gel (mobile phase: toluene/ acetonitrilegradient from 40:1 to 4:1).

Yield: 41 mg(21.1% of theory)

MS (DCI/NH₃): m/z=499 (M+H)⁺

HPLC: R_(t)=7.71 min.

Example 232-(4-Chlorophenyl)-5-(3,5-dihydro-2H-pyridin-1-yl)-4-(4′-fluorobiphenyl-4-yloxy)-2H-pyridazin-3-one

Obtainable by general method 6-c from 90 mg (1.1 mmol) of1,2,5,6-tetrahydro-pyridine and 300 mg (0.702-mmol) of5-chloro-4-(4-fluorophenylphenyloxy)-2-(4-chlorophenyl)-2(3H)-pyridazinone.

Yield: 196 mg (58.8% of theory)

MS (DCI/NH₃): m/z=474 (M+H)⁺

HPLC: R_(t)=10.87 min.

Example 242-(4-Chlorophenyl)-5-(3,4-dihydroxy-1-piperidinyl)-4-[(4′-fluoro-1,1′-biphenyl-4-yl)oxy]-3(2H)-pyridazinone

90 mg (0.753 mmol) of N-methylmorpholine N-oxide and 0.64 ml (0.949mmol) of osmiumtetroxide as 2.5% by weight solution in tert-butanol areadded to a solution of 100 mg (0.211 mmol) of the compound from Example23 in 8 ml of THF, and the mixture is stirred in the dark at roomtemperature overnight. 80 mg of sodium sulfite in 0.5 ml of water arethen added to the reaction mixture, which is diluted with 80 ml ofdichloromethane and 20 ml of sodium chloride solution and stirred for 1h. The organic phase is dried over sodium sulfate and concentrated, andthe residue is purified by chromatography on silica gel usingtoluene/acetonitrile 9:1 as mobile phase. The residue is then stirred inether, filtered off with suction and dried under high vacuum.

Yield: 23 mg (21.5% of theory)

MS (ESI): m/z=508 (M+H)⁺

HPLC: R_(t)=8.71 min.

Example 252-(4-Chlorophenyl)-4-[(4′-fluoro-1,1′-biphenyl-4-yl)oxy]-5-[4-(hydroxymethyl)-1-piperidinyl]-3(2H)-pyridazinone

20.0 g (46.8 mmol) of5-chloro-4-(4-fluorophenylphenyloxy)-2-(4-chlorophenyl)-2(3H)-pyridazinone,6.47 g (56.17 mmol) of 4-hydroxymethylpiperidine, 7.77 g (46.81 mol) ofpotassium iodide and 16.31 ml (93.62 mmol) of ethyldiisopropylamine arestirred in 200 ml of DMF under argon at 12° C. overnight. The reactionmixture is cooled to room temperature, diluted with dichloromethane andwashed three times with water. The organic phase is dried andconcentrated, and the resulting residue is stirred with ether andfiltered off with suction. The crude product is purified bychromatography on silica gel in a gradient process with toluene andtoluene/acetonitrile (from 20:1 via 10:1 to 5:1) as mobile phase.

Yield: 13.2 g (55.7% of theory)

MS (ESI): m/z=506 (M+H)⁺

HPLC: R_(t)=9.50 min.

Example 264-(1,1′-Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5-(1-oxido-4-thiomorpholinyl)-3(2H)-pyridazinone

110 mg (0.308 mmol) of 3-chloroperoxybenzoic acid (57-86% pure) areadded in, portions over the course of 5 min to a solution of 150 mg(0.308 mmol) of2-(4-chlorophenyl)-4-(4-phenylphenyloxy)-5-(thiomorpholinyl-1-)-2(3H)-pyridazinonein 15 ml of dichloromethane, and the mixture is stirred at roomtemperature for 3 h. The reaction solution is then loaded onto about 100ml of dry silica gel and chromatographed with ethyl acetate and ethylacetate/acetone mixtures in the ratio 4:1, 1:1 and 1:4 as mobile phase.

Yield: 56 mg (36.6% of theory)

MS (DCI/NH₃): m/z=492 (M+H)⁺

HPLC: R_(t)=8.68 min.

Example 274-(1,1′-Biphenyl-4-yloxy)-2-(4-chlorophenyl)-5-(1,1-dioxido-4-thiomorpholinyl)-3(2H)-pyridazinone

This compound was obtained as further product in the preparation ofExample 26 and crystallized by trituration with diisopropyl ether.

Yield: 95 mg (52.7% of theory)

MS (ESI): m/z=508 (M+H)⁺

HPLC: R_(t)=9.38 min.

Exemplary embodiments 28-223 listed in table 7 were prepared by generalprocesses 1-17: Example Analysis (data in ° C. General No. Structurerelate to the melting point) process 28

DCI/NH₃: 490 (M + NH₄, 100%) HPLC: rt (%) = 7.38 (99.4) 6a 29

DCI/NH₃: 460 (M + H, 100%) HPLC: rt (%) = 7.88 (98.3) 6a 30

DCI/NH₃: 456 (M + H, 100%) HPLC: rt (%) = 8.34 (78.7) 6a 31

DCI/NH₃: 440 (M + H, 100%) HPLC: rt (%) = 7.64 (98.1) 6a 32

DCI/NH₃: 476 (M + H, 100%) HPLC: rt (%) = 8.50 (97.9) 6a 33

DCI/NH₃: 553 (M + H, 100%) HPLC: rt (%) = 6.72 (94.0) 6a 34

m.p.: 162° C. ESI: 473 (M + H, 100) HPLC: rt (%) 7.42 (99.6) ¹H-NMR (300MHz, DMSO-d₆): δ = 2.7 (s, 3H), 3.0-4.2 (several broad m, 8H), 7.1 (m,2H), 7.3-7.7 (m, 11H), 8.3 (s, 1H) 6a 35

DCI/NH₃: 476 (M + H, 100%) HPLC: rt (%) = 6.72 (96.7) 6a 36

DCI/NH₃: 489 (M + H, 100%) HPLC: rt (%) = 5.40 (93.3) 6a 37

DCI/NH₃: 489 (M + H, 100%) HPLC: rt (%) = 6.74 (100) 6a 38

DCI/NH₃: 503 (M + H, 100%) HPLC: rt (%) = 6.80 (94.1) 6a 39

DCI/NH₃: 487 (M + H, 100%) HPLC: rt (%) = 7.44 (94.7) 6a 40

MS (ESI): 459 (M + H) (free base) HPLC: rt (%) = 7.22 (99.9) 7 41

ESI: 487 (M + H, 100%) HPLC: rt (%) = 7.47 (100) 6a 42

ESI: 503 (M + H, 100%) HPLC: rt (%) = 7.20 (91.2) 6a 43

ESI (CH₃CN/H₂O; 0.1% CH₃COOH): 503 (100%) HPLC: rt (%) = 6.07 (99.6) 6a44

ESI (CH₃CN/H₂O; 0.1% CH₃COOH): 487 (100%) HPLC: rt (%) = 7.42 (95.3) 6a45

ESI (CH₃CN/H₂O; 0.1% CH₃COOH): 487 (100%) HPLC: rt (%) = 6.27 (99.0) 6a46

DCI/NH₃: 592 (M + NH₄, 100%) HPLC: rt (%) = 9.86 (50.8) 6a 47

DCI/NH₃: 492 (M + NH₄, 100%), 475 (M + H, 51%) HPLC: rt (%) = 6.58(88.8) 7 48

ESI (CH₃CN/H₂O; 0.1% CH₃COOH): 501 (M + H, 100%) HPLC: rt (%) = 9.15(91.6) 2 49

DCI/NH₃: 503 (M + H, 100%) HPLC: rt (%) = 6.74 (99.6) 6a 50

DCI/NH₃: 502 (M + NH₄, 100%), 503 (M + H, 67%) HPLC: rt (%) = 6.69 (100)6a 51

DCI/NH₃: 563 (M + NH₄, 100%) HPLC: rt (%) = 9.69 (96.9) 6a 52

ESI (CH₃CN/H₂O; ammonium acetate): 537 (100%) HPLC: rt (%) = 9.75 (98.0)4 53

ESI: 547 (M + H, 100%) HPLC: rt (%) = 9.08 (100) 6a 54

ESI: 517 (100%) HPLC: rt (%) = 7.58 (97.0) 6a 55

DCI/NH₃: 473 (M + H, 100%) HPLC: rt (%) = 7.40 (92.4) 7 56

DCI/NH₃: 473 (M + H) 7 57

DCI/NH₃: 470 (M + H, 100%) HPLC: rt (%) = 7.27 (100) 7 58

HPLC: rt (%) = 7.65 (98.4) 6a 59

ESI: 551 (M + H, 100%) HPLC: rt (%) = 6.96 (98.9) 6a 60

ESI: 502 (M + H, 100%) HPLC: rt (%) = 8.51 (97.5) 5 61

ESI: 527 (M + H, 100%) HPLC: rt (%) = 9.65 (95.9) 2 62

ESI: 530 (M + H, 100%) HPLC: rt (%) = 9.22 (96.6) 6a 63

ESI: 499 (M + H, 100%) HPLC: rt (%) = 7.66 (94.7) 6a 64

ESI: 493 (M + H 100%) HPLC: rt (%) = 7.64 (100) 7 65

ESI: 517 (M + H, 100%) R_(f): 0.30 (toluene/acetonitrile 4:1) 6a 66

DCI/NH₃: 572 (M + H, 100%) HPLC: rt (%) = 6.69 (100) 6a 67

DCI/NH₃: 545 (M + H, 100%) HPLC: rt (%) = 8.24 (99.3) 6a 68

DCI/NH₃: 530 (M + H, 100%) HPLC: rt (%) = 7.28 (73.6) 6a 69

DCI/NH₃: 565 (M + H, 100%) HPLC: rt (%) = 10.12 (76.6) 4 70

ESI: 516 (M + H, 60%) HPLC: rt (%) = 8.90 (99.7) 6a 71

186° C. 16a 72

151° C. 16a 73

148° C. 16a 74

119° C. 16a 75

16a 76

220° C. 16a 77

177° C. 16a 78

188° C. 16a 79

80

276° C. 16a 81

216° C. ¹H-NMR (200 MHz, DMSO-d₆): δ= 6.7 (m, 2H), 7.2-7.3 (m, 3H),7.4-7.8 (m, 9H), 8.25 (s, 1H), 8.70 (s, 1H), 9.5 (s, 1H) 16a 82

188° C. ¹H-NMR (400 MHz, CDCl₃): δ= 7.15 (m, 2H, AA′ of a AA′BB′system),7.2-7.6 (several m, 11H), 7.65 (m, 2H, BB′ of a AA′BB′system), 8.1 (s,1H), 8.2 (s, 1H) 16c 83

180° C. 16a 84

MS (B): 481 (M + H) (100) HPLC: 8.77 (99) 2 85

MS (B): 499 (M + H) (100) HPLC: 8.84 (100) 2 86

MS (A): 484 (M + H) (100) HPLC: 7.45 (98) 3 87

MS (B): 467 (M + H) (100) HPLC: 8.73 (99) 3 88

MS (B): 485 (M + H) (100) HPLC: 8.80 (86) 3 89

MS (B): 534 (M + H) (100) HPLC: 7.83 (100) 4 90

MS (B): 517 (M + H) (100) HPLC: 9.38 (97) 4 91

MS (B): 535 (M + H) (100) HPLC: 9.44 (94) 4 92

MS (D): 615 (M + H) (100) HPLC: 9.75 (86) 4 93

MS (E): 612 (M + H) (100) HPLC: 8.47 (92) 4 94

MS (E): 608 (M + H) (100) HPLC: 8.30 (92) 4 95

MS (D): 573 (M + H) (100) HPLC: 9.75 (98) 4 96

MS (D): 567 (M + H) (100) HPLC: 9.62 (96) 4 97

MS (D): 626 (M + H) (100) HPLC: 8.34 (100) 4 98

MS (D): 585 (M + H) (100) HPLC: 9.71 (95) 4 99

MS (D): 608 (M + H) (100) HPLC: 8.19 (100) 4 100

MS (B): 482 (M + H) (100) HPLC: 8.21 (98) 5 101

MS (B): 500 (M + H) (100) HPLC: 8.28 (89) 5 102

MS (B): 455 (M + H) (100) HPLC: 4.98 (96) 7 103

MS (B): 439 (M + H) (100) HPLC: 6.89 (95) 7 104

MS (B): 457 (M + H) (100) HPLC: 7.12 (95) 7 105

MS (B): 457 (M + H) (100) HPLC: 7.90 (93) 10 106

MS (B): 475 (M + H) (100) HPLC: 3.78 (99) 10 107

MS (B): 519 (M + H) (100) HPLC: 6.48 (100) 10 108

MS (B): 519 (M + H) (100) HPLC: 6.53 (91) 10 109

MS (B): 519 (M + H) (100) HPLC: 6.65 (98) 10 110

MS (B): 537 (M + H) (100) HPLC: 6.84 (100) 10 111

MS (B): 493 (M + H) (100) HPLC: 6.86 (91) 10 112

MS (B): 535 (M + H) (100) HPLC: 8.45 (98) 10 113

MS (D): 517/519 (M + H) (100) HPLC: 7.89 (94) 10 114

MS (A): 571 (M + H) (100) HPLC: 9.01 (99) 10 115

MS (A): 561 (M + H) (100) HPLC: 8.97 (96) 10 116

MS (A): 515 (M + H) (100) HPLC: 8.18 (99) 10 117

MS (D): 520 (M + H) (100) HPLC: 8.72 (100) 10 118

MS (D): 549/551 (M + H) (100) HPLC: 9.31 (99) 11 119

MS (A): 575 (M + H) (100) HPLC: 9.72 (97) 11 120

MS (B): 529 (M + H) (100) HPLC: 8.89 (95) 11 121

MS (A): 455 (M + H) (100) HPLC: 7.94 (94) 16a 122

MS (A): 489 (M + H) (100) HPLC: 10.15 (94) 16a 123

MS (A): 455 (M + H) (100) HPLC: 8.15 (95) 16a 124

MS (B): 502 (M + H) (100) HPLC: 8.69 (98) 14 125

MS (B): 472 (M + H) (100) HPLC: 9.33 (99) 14 126

MS (B): 500 (M + H) (100) HPLC: 10.20 (98) 14 127

MS (B): 442 (M + H) (100) HPLC: 10.12 (96) 14 128

MS (B): 472 (M + H) (100) HPLC: 9.20 (84) 14 129

MS (B): 500 (M + H) (100) HPLC: 10.21 (96) 14 130

MS (D): 552/554 (M + H) (100) HPLC: 10.60 (97) 14 131

MS (A): 504 (M + H) (100) HPLC: 9.37 (98) 14 132

MS (B): 504 (M + H) (100) HPLC: 9.16 (100) 14 133

MS (B): 522 (M + H) (100) HPLC: 9.78 (96) 14 134

MS (B): 564 (M + H) (100) HPLC: 9.94 (99) 14 135

MS (D): 522 (M + H) (100) HPLC: 9.22 (94) 14 136

MS (B): 563 (M + ) (38) HPLC: 9.67 (99) 14 137

MS (B): 498 (M + H) (100) HPLC: 7.58 (96) 2 138

MS (A): 539 (M + H) (100) HPLC: 10.89 (98) 6-a 139

MS (B): 557 (M + H) (100) 6-a 140

MS (B): 473 (M + H) (100) HPLC: 9.25 (94) 9-a 141

MS (A): 473 (M + NH₄) (100), 456 (M + H) (52) HPLC: 6.64 (97) 9-a 142

MS (B): 521 (M + H) (100) HPLC: 7.45 (98) 9-a 143

MS (D): 490 (M + H) (100) HPLC: 9.36 (99) 9-a 144

MS (A): 442/444 (M + H) (100) HPLC: 6.75 (98) 9-b 145

MS (C): 500 (M) (100) HPLC: 8.80 (97) 9-b 146

MS (B): 541 (M + Na) (100), 519 (M + H) (74) HPLC: 8.95 (96) 9-b 147

MS (B): 504 (M + H) (100) HPLC: 5.20 (96) 9-b 148

MS (B): 457 (M + H) (100) HPLC: 5.93 (95) 9-b 149

MS (A): 518 (M + H) (100) HPLC: 5.55 (96) 9-b 150

MS (B): 471 (M + H) (100) HPLC: 7.71 (96) 9-b 151

MS (B): 532 (M + H) (100) HPLC: 5.32 (96) 9-b 152

MS (B): 533 (M + H) (100) HPLC: 6.68 (99) 9-b 153

MS (A): 563 (M + H) (100) HPLC: 7.30 (97) 9-b 154

MS (A): 581 (M + H) (100) HPLC: 7.51 (96) 9-b 155

MS (B): 578 (M + H) (100) HPLC: 6.51 (93) 9-b 156

MS (D): 456 (M + H) (100) HPLC: 3.83 (97) 9-b 157

MS (D): 459/461 (M + H) (100) HPLC: 4.47 (100) 9-b 158

MS (D): 477/479 (M + H) (100) HPLC: 4.53 (100) 9-b 159

MS (D): 471/473 (M + H) (100) HPLC: 4.45 (100) 9-b 160

MS (D): 474 (M + H) (100) HPLC: 4.05 (98) 9-b 161

MS (F): 517 (M + H) (100) 9-b 162

MS (F): 533 (M + H) (100) 9-b 163

MS (F): 518 (M + H) (100) 9-b 164

MS (F): 560 (M + H) (100) 9-b 165

MS (F): 533 (M + H) (100) 9-b 166

MS (F): 545 (M + H) (100) 9-b 167

MS (F): 536 (M + H) (100) 9-b 168

MS (F): 518 (M + H) (100) 9-b 169

MS (B): 489 (M + H) (100) HPLC: 6.60 (98) 9-c 170

MS (A): 489 (M + H) (100) HPLC: 6.48 (98) 9-c 171

MS (B): 489 (M + H) (100) HPLC: 6.37 (96) 9-c 172

MS (B): 534 (M + H) (100) HPLC: 6.55 (97) 9-c 173

MS (B): 488 (M + H) (100) HPLC: 6.33 (99) 9-c 174

MS (B): 506 (M + H) (100) HPLC: 5.39 (98) 9-c 175

MS (B): 530 (M + H) (100) HPLC: 6.54 (100) 9-c 176

MS (B): 548 (M + H) (100) HPLC: 6.55 (98) 9-c 177

MS (B): 537 (M + H) (100) HPLC: 7.46 (94) 9-c 178

MS (B): 579 (M + H) (100) HPLC: 9.21 (93) 9-c 179

MS (B): 561 (M + H) (100) HPLC: 8.91 (99) 9-c 180

MS (E): 549 (M + H) (100) HPLC: 8.04 (97) 9-c 181

MS (B): 495 (M + H) (100) HPLC: 7.47 (94) 9-c 182

MS (B): 489 (M + H) (100) HPLC: 7.25 (92) 9-c 183

MS (D): 507 (M + H) (100) HPLC: 7.40 (91) 9-c 184

MS (D): 530 (M + H) (100) HPLC: 6.37 (96) 9-c 185

MS (A): 545 (M + H) (100) HPLC: 9.67 (92) 9-c 186

MS (A): 563 (M + H) (100) HPLC: 9.77 (91) 9-c 187

MS (D): 575 (M + H) (100) HPLC: 8.57 (97) 9-c 188

MS (D): 528 (M + H) (100) HPLC: 6.55 (95) 9-c 189

MS (A): 605 (M + H) (100) HPLC: 9.74 (99) 9-c 190

MS (A): 502 (M + H) (100) HPLC: 6.16 (92) 9-c 191

MS (A): 517 (M + H) (100) HPLC: 8.93 (98) 9-c 192

MS (A): 483 (M + H) (100) HPLC: 6.79 (98) 9-c 193

MS (A): 559 (M + H) (100) HPLC: 8.92 (97) 9-c 194

MS (F): 537 (M + H) (100) HPLC: 4.59 (100) 9-c 195

MS (F): 533 (M + H) (100) HPLC: 4.69 (100) 9-c 196

MS (F): 519 (M + H) (100) HPLC: 4.51 (100) 9-c 197

MS (F): 531 (M + H) (100) HPLC: 4.50 (100) 9-c 198

MS (F): 515 (M + H) (100) HPLC: 4.64 (100) 9-c 199

MS (F): 531 (M + H) (100) HPLC: 4.47 (100) 9-c 200

MS (F): 531 (M + H) (100) HPLC: 3.99 (93) 9-c 201

MS (F): 531 (M + H) (100) HPLC: 3.92 (94) 9-c 202

MS (F): 558 (M + H) (100) HPLC: 3.90 (100) 9-c 203

MS (F): 576 (M + H) (100) HPLC: 3.94 (93) 9-c 204

MS (F): 558 (M + H) (100) HPLC: 3.84 (100) 9-c 205

MS (F): 612 (M + H) (100) HPLC: 4.01 (100) 9-c 206

MS (F): 594 (M + H) (100) HPLC: 4.02 (100) 9-c 207

MS (F): 572 (M + H) (100) HPLC: 3.87 (100) 9-c 208

MS (F): 590 (M + H) (100) HPLC: 3.90 (100) 9-c 209

MS (F): 572 (M + H) (100) HPLC: 3.84 (100) 9-c 210

MS (F): 534 (M + H) (100) HPLC: 4.00 (100) 9-c 211

MS (F): 530 (M + H) (100) HPLC: 3.27 (100) 9-c 212

MS (F): 548 (M + H) (100) HPLC: 3.28 (100) 9-c 213

MS (C): 481 (M + H) (100); HPLC: 8.77 (98) 3 214

MS (C): 482 (M + H) (100); HPLC: 8.22 (82) 5 215

MS (C): 517 (M + H) (100); HPLC: 9.38 (97) 4 216

MS (C): 499 (M + H) (100); HPLC: 8.84 (100) 2 217

MS (C): 500 (M + H) (100); HPLC: 8.28 (89) 5 218

MS (C): 535 (M + H) (100); HPLC: 9.44 (94) 4 219

MS (C): 467 (M + H) (100); HPLC: 8.73 (99) 3 220

MS (C): 485 (M + H) (100); HPLC: 8.80 (86) 3 221

MS (C): 558 (M + H) (100); HPLC: 10.32 (99) 14 222

1 223

MS (C): 582 (M + H) (100); HPLC: 7.39 (96) 1

1. A compound of the formula (I)

in which R¹ is 5- to 7-membered, saturated or partially unsaturated heterocyclyl which is linked via a ring nitrogen atom and optionally has a further heteroatom or hetero chain member from the series N, O, S, SO or SO₂, and which may be substituted once or twice, identically or differently, by substitutents selected from the group of halogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, hydroxy, oxo, carboxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, (C₃-C₈)-cycloalkylcarbonyl, (C₁-C₆)-alkylsulfonyl, aminocarbonyl,

and (C₁-C₆)-alkylaminocarbonyl, where (C₁-C₆)-alkyl and (C₁-C₆)-alkanoyl in turn may each be substituted by halogen, hydroxy, (C¹-C₄)-alkoxy, (C₁-C₄)-alkoxycarbonyl, amino, mono- or di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkoxycarbonylamino or 5- or 6-membered heterocyclyl having up to two heteroatoms from the series N, O and/or S, or R¹ is 5-membered heteroaryl which is linked via a ring nitrogen atom and has up to two further ring nitrogen atoms, and which may be substituted once to three times, identically or differently, by halogen, (C₁-C₆)-alkoxycarbonyl or (C₁-C₆)-alkyl which is in turn optionally substituted by hydroxy or halogen, R² is (C₆-C₁₀)-aryl which may be substituted once or twice, identically or differently, by substituents selected from the group of halogen, nitro, cyano, (C₁-C₆)-alkyl, trifluoromethyl, (C₁-C₆)-alkanoyl, (C¹-C₆)-alkoxy, hydroxy, (C₁-C₆)-acyloxy, amino, (C₁-C₆)-acylamino, mono- and di-[(C₁-C₆)-alkylsulfonyl]amino, where (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy in turn may each be substituted by hydroxy, amino, (C₁-C₄)-alkoxy or (C₁-C₄)-acylamino, or R² is 5- or 6-membered heteroaryl which has up to two ring nitrogen atoms and which may be substituted by amino, hydroxy, halogen, (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy, and R³ is hydrogen, halogen, (C₁-C₆)-alkyl, trifluoromethyl, nitro, cyano, carboxyl or (C₁-C₆)-alkoxycarbonyl, or a salt, solvate or solvate of a salt thereof.
 2. The compound of the formula (I) as claimed in claim 1, in which R¹ is a group of the formula

in which A is CR⁴R⁵, O, S, NR⁶ or —CH₂NR⁶—, where R⁴ and R⁵ are independently of one another hydrogen, (C₁-C₄)-alkyl, which may be substituted by hydroxy, or hydroxy, fluorine, carboxyl or (C₁-C₄)-alkoxycarbonyl, or together with the carbon atom to which they are bonded form a carbonyl group, and R⁶ is hydrogen, (C₂-C₄)-alkenyl, (C₃C₆)-cycloalkyl, (C₁-C₄)-alkoxycarbonyl, formyl, acetyl, (C₃-C₆)-cycloalkylcarbonyl, (C₁-C₄)-alkylsulfonyl, aminocarbonyl, (C₁-C₄)-alkylaminocarbonyl or is (C₁-C₄)-alkyl which in turn may be substituted by hydroxy, methoxy, ethoxy, (C₁-C₄)-alkoxycarbonyl, amino, dimethylamino, diethylamino, pyrrolidino, piperidino or morpholino, or R¹ is 5-membered heteroaryl which is linked via a ring nitrogen atom and has up to two further ring nitrogen atoms and which may be substituted once or twice, identically or differently, by fluorine, chlorine, (C₁-C₄)-alkoxycarbonyl or (C₁-C₄)-alkyl which in turn is optionally substituted by hydroxy, R² is phenyl which may be substituted once or twice, identically or differently, by substituents selected from the group of fluorine, chlorine, cyano, (C¹-C₄)-alkyl, trifluoromethyl, formyl, acetyl, (C₁-C₄)-alkoxy, hydroxy, acetoxy, pivaloyloxy, amino, formylamino, acetylamino and methylsulfonylamino, where (C₁-C₄)-alkyl and (C₁-C₄)-alkoxy in turn may each be substituted by hydroxy, amino, methoxy, ethoxy or acetylamino, or R² is pyrrolyl, pyridyl or pyrimidinyl, each of which may be substituted by amino, fluorine, chlorine, methyl, ethyl, methoxy or ethoxy, and R³ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, nitro or cyano, or a salt, solvate or solvate of a salt thereof.
 3. The compound of the formula (I) as claimed in claim 1, in which R¹ is imidazolyl which is attached via a ring nitrogen atom or is piperazinyl which is attached via a ring nitrogen atom and which may be substituted on the second ring nitrogen atom by methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, acetyl, tert-butoxycarbonyl or methylsulfonyl, R² is phenyl which may be substituted by fluorine or hydroxy in position 4 relative to the linkage point on the phenyl ring, and R³ is located in position 4 relative to the linkage point of the pyridazinone ring and is hydrogen, fluorine, chlorine, methyl or trifluoromethyl, or a salt, solvate or solvate of a salt thereof.
 4. The compound of the formula (I) as claimed in claim 1, wherein the compound has one of the following structures:

or a salt, solvate or solvate of a salt thereof.
 5. A process for preparing the compounds of the formula (I) as defined in claim 1, wherein first compounds of the formula (II)

in which R³ has the meaning indicated in claim 1, and X¹ and X² are each halogen, are converted with a compound of the formula (III) R¹—H  (III), in which R¹ has the meaning indicated in claim 1, into compounds of the formula (IV)

in which R¹, R³ and X² each have the meaning indicated above, and the latter are then reacted with a compound of the formula (V)

in which R² has the meaning indicated in claim
 1. 6. (canceled)
 7. A medicament comprising at least one compound of the formula (I) as defined in claim 1, and at least one further excipient.
 8. A medicament comprising at least one compound of the formula (I) as defined in claim 1, and at least one further active ingredient.
 9. A method for treating or preventing fibrotic disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim
 1. 